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NIOSH Program Portfolio

 

Manufacturing

NORA Manufacturing Sector Strategic Goals

927ZJHFa - Assessment of Engineered Materials on Respiratory Immunity (NTRC)

Start Date: 10/1/2009
End Date: 9/30/2012

Principal Investigator (PI)
Name: Anna Shvedova
Phone: 304-285-6177
E-mail: ats1@cdc.gov
Organization: NIOSH
Sub-Unit: HELD
Funded By: NIOSH

Primary Goal Addressed
9.0

Secondary Goal Addressed
None


Attributed to Manufacturing
100%

Project Description

Short Summary

A preliminary study of biological effects of Single Walled Carbon Nanotubes (SWCNT) in vitro and in vivo revealed clear interaction between Engineered Nanomaterials (ENs) and immune cells affecting their primarily function. In particularly, it was found that SWCNT suppressed innate immunity associated with reduced recognition of the particles and bacteria by alveolar macrophages, suppressed ROS production and decreased bacterial clearance causing extended pulmonary inflammation, inpaired innate immunity and lung lesions. The results of these studies will benefit to hazard characterization and risk assessment of ENs with respect to immune outcomes, based on the following steps: a) analysis of the most important physico-chemical characteristics of the tested ENs influencing the response in vitro; b) extrapolation of in vitro results to the in vivo situations using appropriate scaling algorithms; c) extrapolation of the animal-based model systems to human exposures. Overall, the project objective is to perform a comprehensive assessment of adverse respiratory immune effects of selected ENs in order to understand how the benefits of the emerging nanotechnologies can be realized while minimizing potential risks to human health during manufacturing.



Description

In the last four years, the federal government has provided over one billion dollars in nanotechnology research funding. ENs are among these newly developed products and are currently of interest for a variety 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 (4). Introduction of novel materials into industry requires evaluating safety and understanding the impact of nanomaterials on the environment, biological species and human health. The objective of this work is to evaluate the pulmonary toxicological effects of ENs both in vitro and in vivo. The project has 3 aims: 1) in vitro assessment of cellular and molecular mechanisms of adverse effects of ENs on cells of immune origin, with emphasis on modes of cell death (apoptosis, necrosis), mediators of cell death and other toxicities (oxidative stress, genotoxic effects), and consequences of EN exposure at the cellular level (recognition and uptake of ENs by phagocytes, cytokine responses, effects on interactions between antigen presenting cells and lymphocytes, etc); 2) evaluation of the biological behavior of different ENs in animal models in respect to immune pulmonary response, using established dose-response relationships/mechanisms to build a database to support risk assessment and recommendations for a safe level for worker exposure; 3) development and validation of high-throughput, array-based methodologies for the assessment and prediction of outcomes (“immune-nanotoxicity-signatures”) of EN exposure to immune-competent cells in vitro and in vivo.



Time Frame for completing each Specific Aims of the project is as follows:



Assessment of cellular and molecular mechanisms of adverse effects of ENs in vitro (Specific Aim 1) will be performed during 0 – 12th month. The evaluation of the biological behavior of different ENs in animal models (Specific Aim 2) will be completed during the 7th-30th month. The development and validation of array-based methodologies for the assessment and prediction of outcomes of exposure of immune-competent cells in vitro and in vivo to ENs (Specific Aim 3) will be assessed during 18th-36th month.



Project outputs will be collection of data to achieve the three project goals outlined above, to present data at scientific conferences, and to publish data in peer review journals. Such publications will influence future direction of studies on ENs by the scientific community. Mechanistic, dose-response, and time course information will be transmitted to NASA, NTRC, and EU FW7 to assist in the evaluation of health risk and the implementation of hygiene and prevention measures. Outcomes will be impact on the direction of the research by the scientific community as judged by citations and use of results to guide NIOSH recommendations for the safe handling and use of ENs.



Objectives

Although nanotechnology contributes to a number novel applications, devises as well as products, it's wide production and use may lead to an environmental and occupation exposure burden caused by exposure during manufacturing processes and disposal. The past decade of investment and development of nanotechnology in the US illustrates the growing importance and recognition of this emerging science, which has now gotten a strong foothold in many of the country's leading research institutions. Introduction of novel materials into industry requires evaluation of safety and an understanding of the impact of nanomaterials on the environment, biological species and human health. Nanosized and ultrafine particles are deemed more toxic because of their ability to reach the alveolar space affecting a large surface area of the lung, and their ability to penetrate and reside in distant immune origin and other organs causing unpredicted extensive inflammatory responses. To date very limited information is available concerning the potential immune toxicity of ENs. The objective of this work is to evaluate the pulmonary toxicological effects of ENs both in vitro and in vivo. The project has 3 aims: 1) in vitro assessment of cellular and molecular mechanisms of adverse effects of ENs on cells of immune origin, with emphasis on modes of cell death (apoptosis, necrosis), mediators of cell death and other toxicities (oxidative stress, genotoxic effects), and consequences of EN exposure at the cellular level (recognition and uptake of ENs by phagocytes, cytokine responses, effects on interactions between antigen-presenting cells and lymphocytes, etc); 2) evaluation of the biological behavior of different ENs in animal models with respect to immune pulmonary response, using established dose-response relationships/mechanisms to build a database to support risk assessment and recommendations for a safe level for worker exposure; 3) development and validation of high-throughput, array-based methodologies for the assessment and prediction of outcomes (“immune-nanotoxicity-signatures”) of EN exposure to immune competent cells in vitro and in vivo. 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. When 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 ENs, introduction of tests for the potential toxicity of ultrafine materials and the development of preventative strategies targeting adverse pulmonary outcomes. This information will be disseminated to NASA, NTRC, and EU FW7 and to industry via articles in the lay press and summaries on the NIOSH Nanotechnology Website. Impact will be evaluated by citations of these publications by extramural scientists and the use of results in instituting safe work practices and prevention measures in the workplace.



Mission Relevance

Engineered nanomaterials (ENs) are valuable sources for numerous industrial (polymer composites, reinforced rods, microfabricating conjugated polymer activators, supersensitive sensors, e.g.) and biomedical applications (bone substitutes, biomimetic composites, drug delivery, chemical and genetic probes). ENs are already in consumer products, such as sun screens, pharmaceuticals, cosmetics and toiletry products, which are used daily by millions. 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 evaluations of safety and understanding of the impact of nanomaterials on the environment, biological species and human health.

To date workplace exposure to various nanoparticles has been conducted to a limited extent. However, surveillance of workers is absent.

To date, little information is available concerning the potential immune toxicity of engineered nanomaterials. These considerable gaps in our knowledge concerning the potential hazardous immune-respiratory effects of engineered nanomaterials have been noted by the National Nanotechnology Initiative (a multi-agency framework to ensure US leadership in nanotechnology), and by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) at the European Commission. Studies of immune-respiratory effects of engineered nanomaterials also respond to the Strategic Goals of the NIOSH Manufacturing Sector and Respiratory Diseases and Nanotechnology Cross-Sectors to address the following goals: 1) develop predictive models for toxicity, 2) determine particle characteristics associated with toxicity, and 3) provide dose-response information to support risk assessment.



Page last updated: June 3, 2011
Page last reviewed: May 23, 2011
Content Source: National Institute for Occupational Safety and Health (NIOSH) Office of the Director

 

NIOSH Program:

Manufacturing