NORA Manufacturing Sector Strategic Goals
927ZGFY - Assessment of Carbonaceous Materials on MutagenicityStart Date: 10/1/2008
End Date: 9/30/2009
Principal Investigator (PI)Name: Anna Shvedova
Funded By: NIOSH
Primary Goal Addressed9.0
Secondary Goal Addressed
Attributed to Manufacturing
Exposure to ultrafine particles has been linked to respiratory diseases, cardiovascular diseases and lung cancer. Lung cancer is currently the leading cause of cancer mortality in the United States. A preliminary study revealed potential mutagenicity of SWCNT and some hyperplasia in the lung of tumor-resistant mice exposed SWCNT. Therefore, a more complete study is required to determine the mutagenic/carcinogenic potential of EN in the lung. Elucidation of mechanisms involved in lung cancer development may lead to the strategies for early detection in susceptible workers. Data obtained from these studies will address Respiratory Disease, Cancer, and Nanotechnology issues and be used for hazards identification, risk assessment and management of carbonaceous EN with respect to occupational exposures and will be used by regulatory agencies (OSHA and EPA) and industry to address strategies for assurance of healthy work practices and safe environment in the Manufacturing Sector.
Carbonaceous EN are among these newly developed products that are currently of high interest for a number of applications in electronics, reinforced rods, micro-fabricating conjugated polymer activators, supersensitive sensors, enhanced electron/scanning microscopy imaging techniques, and biosensors. Nanostructured or microstructured materials are valuable sources for bone substitutes, bio-mimetic composites, chemical and genetic probes (1). EN particles are already widely used in consumer products such as sun screens, cosmetics and toiletries which are used daily by millions, and the market for these materials is estimated to grow to over eight billion dollars in the next decade. Introduction of novel materials into industry requires evaluating safety and understanding the impact of nanomaterials on the environment, biological species and human health. To date, little information is available concerning the potential mutagenicity of nanotubes. Considering the large number of workers employed in the nanotechnology workforce, there are significant knowledge gaps concerning the hazard identification, hazard assessment, risk assessment and management of nanomaterials as noted by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) at the European Commission. This project also responds to the Strategic Goals of the NIOSH Nanotechnology Research Center by evaluating potential mutagenicity of carbonaceous engineered nano-materials (EN). We have previously reported that pharyngeal aspiration exposure of C57BL/6 mice to SWCNT caused dose-dependent formation of granulomatous bronchial interstitial pneumonia, fibrosis, oxidative stress, acute inflammatory cytokine responses and decreased pulmonary function. Furthermore, we have demonstrated that inhalation exposure to aerosolized SWCNT induces pulmonary toxicity and early fibrosis in the lung of C57BL/6 mice. In addition, our preliminary data analysis of lung tissues from these exposed mice showed mutations in the K-ras gene locus similar to those reported in lung tumors of susceptible mice treated with lung carcinogens. Taken together, these results suggest that exposure to SWCNT may lead to the development of pulmonary toxicity, fibrosis, and potentially lung tumors in susceptible mice. Therefore, in this study we hypothesize that exposure of susceptible mouse model FBV/N to SWCNT will lead to pulmonary toxicity and genetic changes, including K-ras mutations, in the lung. Furthermore, we hypothesize that these mutations represent early events in lung tumorigenesis in susceptible mice treated with SWCNT. An associated health hazard of carbonaceous EN to workers has not been investigated in respect to their potential tumorigenesis.
The objective of this work is to evaluate potential mutagenicity of proposed carbonaceous EN. Consequently, the following specific aims of the proposal are:
1) To analyze K-ras mutations in lung tissues (and tumors) obtained from lung of tumor-resistant C57BL/6 mice and lung of tumor-susceptible FBV/N mice at different time points after EN-treatment
2) To assess development of lung cancer after inhalation exposure to carbonaceous EN using tumor susceptible, FVB/N and resistant C57BL/6 mice and their time-dependent association with inflammatory response and fibrosis.
Results obtained from these studies provide critical knowledge about the mechanisms of mutagenic effects of EN and will be used for hazard identification, risk assessment and management. Initial outputs from the project will be abstracts and presentations followed by scientific publications. Scientific impact of such publications will be evaluated by the number of citations by extramural scientists. If the major goals are accomplished, the impact of the study will be to identify new workplace hazards, improve the assessment of risk for workplace exposures to carbon nanotubes induced mutagenicity targeting of pulmonary exposure and development of cancer.
Outputs of this project will be presentations and publications of the result in scientific conferences and journals. Outcomes will impact of results on the state of science in the field, impact on the direction of scientific research by other institutions, impact on recommendations by NIOSH on "Good Handling Practice for Nanomaterials", and impact on development of prevention strategies and risk assessment efforts by NIOSH, OSHA, EPA, and DOD.
Achievement of project goals will be determined by: 1) completion of project milestones, 2) number of presentations and publications, 3) the number of times these outputs are cited by the scientific community and/or mentioned in the lay press, 4) the influence on NIOSH publications such as "Frequently Asked Questions" and "Good Workplace Practices" documents, and 5) the usefulness in development of prevention strategies and risk assessment efforts by NIOSH, OSHA, EPA, and DOD. This information will be transmitted to NASA via an Interagency Agreement and to industry via articles in the lay press and summaries on the NIOSH Nanotechnology Web site. The importance of mutagenicity tests has been noted by Environmental health and Safety Workgroup of NEHI as part of National Natotechnology Initiative guidelines.
The nanotechnology is a multibillion dollar industry expecting to grow reaching a trillion dollars investment by 2015. Introduction of novel materials into industry requires evaluating safety and understanding of the impact of nanomaterials on the environment, biological species and human health. To date, little information is available concerning the potential mutagenic toxicity of carbonaceous materials including carbon nanotubes. An associated health hazard of carbonaceous EN to workers has not been investigated with respect to their potential tumorigenesis. Considering the large number of workers employed in the nanotechnology workforce, there are significant knowledge gaps concerning the hazard identification, hazard assessment, risk assessment and management of nanomaterials as noted by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) at the European Commission. NIOSH Nanotechnology Research Center (NTCR) which identified critical issues by developing a strategic plan of goals and objectives required to build an informative data base necessary to develop prevention strategies and protect the health of workers involved in the production and use of nanomaterials. Because of high potential for use of carbonaceous EN in a number of novel applications, the NTCR listed the evaluation of the bioactivity/toxicity of carbonaceous EN as an important research objective. This project also responds to Strategic Goal 1 of Nanotechnology (100%) by evaluating potential mutagenicity of carbonaceous EN. "Determine whether nanoparticles and nanomaterials pose risks of injuries and illnesses for workers." Intermediate Goal 2.1 (09PPNANIG2.1) "Key factors and mechanisms". Performance Measure 2.1 "Determine the genotoxic and carcinogenic effects of SWCNT". Research results will address Strategic Goal 9 of the Manufacturing Sector (100%) "Enhance the state of knowledge related to occupational safety and health in manufacturing." The project will also address Strategic Goal 5 of Respiratory Disease Cross Sector (50%) "Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials." Intermediate Goal 5.1 (09PPRDRIG5.1) "Determine the potential respiratory toxicities of nanomaterials". Activity/Output Goal 5.1.1 (09PPRDRAOG 5.1.1) "Perform basic in vitro and in vivo toxicology studies". The project will also address strategic Goal 1 of the Cancer Cross Sector (50%) "Reduce the incidence of work-related cancer." Intermediate Goal 1.1 (09PPCRCIG1.1) "Conduct research to reduce work-related cancer" Activity/Output Goal 1.1.3 (09PPCRCAOG1.1.3) "Develop and evaluate biomonitoring methods". Results obtained from these studies would provide critical knowledge about the mechanisms of mutagenic effects of EN and will be used for hazard identification, risk assessment and management.
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