NORA Manufacturing Sector Strategic Goals
927ZGGA - Nanoparticle Properties and Mechanisms Causing Lung Fibrosis
Principal Investigator (PI)
Primary Goal Addressed
Secondary Goal Addressed
Attributed to Manufacturing
The rapid fibrosis induced by carbon-nanotubes in mice brings up a challenge since information is lacking which would allow one to predict the biological activity of these new nanomaterials. This project will investigate potential fibrogenicity of carbon-nanotubes using both in vitro and in vivo approaches. The in vitro potency sequence of nanotubes of different diameter, aspect ratio, or dispersion status will be compared with their fibrogenic potential in vivo. These results will provide key information about the fibrogenic mechanisms of carbon-nanotubes and validate a set of in vitro screening assays to predict the fibrogenic potential of nanoparticles; thus, supporting risk assessment concerning Respiratory Disease and Nanotechnology issues within the Manufacturing Sector.
Potential adverse health effects of nanoparticles on exposed workers are not known, and information is lacking which would allow one to predict the biological activity of these new nanomaterials. Previous in vivo data indicate that exposure to SWCNT results in rapid and progressive interstitial fibrosis with only transient inflammation. In vitro screening tests for inflammation and oxidant stress have failed to predict this fibrogenic reaction. Therefore, understanding mechanisms of this unusual fibrogenicity is essential for risk assessment. Furthermore development of in vitro screening tests which would be predictive of fibrogenic potential of nanoparticles is essential.
Based on our previous finding that DSWCNT can rapidly enter to interstitial tissue and cause fibrosis as early as one week post exposure, our hypothesis is that carbon nanotubes, due to their unique diameter, aspect ratio and chemical composition, escape macrophage phagocytosis and penetrate the alveolar epithelial barrier into interstitial tissues. There, they form a matrix that directly stimulates collagen production by fibroblasts. This project will evaluate the predictive value of in vitro assays (penetration across an alveolar epithelial monolayer, ability to escape macrophage phagocytosis, and ability to induce pro-fibrogenic factor secretion from lung cells) for assessing pulmonary fibrogenic potential. Carbon-nanotubes with various physicochemical properties such as diameter, aspect ratio and dispersion status will be tested. The potency sequence of these carbon-nanotubes in vitro will be compared with their potency to cause interstitial fibrosis in vivo.
Determining the physicochemical characteristics of nanoparticles and biological mechanisms involved in nanoparticle induced interstitial fibrosis.
Project achievement will be evaluated by:
> Project results-evaluated by completion of the specific goals;
> Presentation and publication of the results-evaluated by citations by the scientific community;
> Usefulness as a tool for screen toxicity of nanomaterial in workplace-evaluated by adoption by other agencies;
> Influence in hazard identification and risk assessment of nanomaterials-evaluated by impact on NIOSH risk assessment and recommendation at good handling practices and control measures.
The emerging growth of nanotechnology is driving the production of numerous new nanoparticles for a variety of applications in electronics, material fabrication, medical applications, etc.
To date, the potential adverse health effects of nanoparticles on exposed workers are not known. In addition, information is lacking which would allow one to predict the biological activity of these new nanomaterials. Previous in vivo data indicate that exposure to SWCNT results in unexpectedly rapid and progressive interstitial fibrosis with only transient inflammation. However, in vitro screening tests for inflammation and oxidant stress have failed to predict this fibrogenic reaction. Therefore, understanding mechanisms of this unusual fibrogenicity is critical for risk assessment. In addition, development of in vitro screening tests which would be predictive of fibrogenic potential of nanoparticles is essential.
The objective of this project is to develop a set of in vitro screening tests for the fibrogenic potential of carbon nanotubes and to determine the ability of such in vitro tests to predict in vivo fibrogenic response. Results of this project will support the goals of the Manufacturing Sector (100%), Goal 9 "Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing."
Results also support the Respiratory Disease Cross Sector (100%), Goal 2 "Prevent and reduce work-related interstitial lung disease;" Intermediate Goal 2.3 (09PPRDRIG2.3) "Prevent and reduce fiber-induced respiratory disease," and Goal 5 "Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials." Intermediate Goal 5.1 (09PPRDIG5.1) "Determine the potential respiratory toxicities of nanomaterials" Activity/Output Goal 5.1.1 (09PPRDRAOG5.1.1) "Perform in vitro … toxicology studies".
Lastly, the project supports Nanotechnology, Goal 1 "Determine if nanoparticles and nanomaterials pose risks for work-related illnesses." Intermediate Goal 2.2 (09PPNANIG2.2) "Predictive models for toxicity "Performance Measure 2.2 "Develop in vitro assays for …fibrogenic potential".