NORA Manufacturing Sector Strategic Goals
927ZBDH - Occupational exposures and potential neurological risksStart Date: 10/1/2007
End Date: 9/30/2012
Principal Investigator (PI)Name: Krishnan Sriram
Funded By: NIOSH
Primary Goal Addressed5.0
Secondary Goal Addressed9.0
Attributed to Manufacturing
Occupational exposure to aerosolized ultrafine and fine particulates can result in translocation of these materials to the brain and elicit transient, irreversible, or progressive damage to the nervous system. Currently, there is limited information on the adverse neurotoxicological effects of industrial materials, especially engineered nanomaterials. To predict and reduce the risk of occupational illnesses, it is important to establish their neurotoxicity. This project will evaluate neurological effects of ultrafine and fine particles generated at the workplace. A 3-tier approach to evaluate neurotoxicity will be implemented. The project supports the strategic goals of MNF and CON Sectors, as well as, CRC, NAN and EXA cross-sectors. Results from this study will aid in development of bio-monitoring protocols, hazard and risk assessment paradigms and significantly contribute to occupational safety standards.
The concerns over potential neurological effects of occupational exposure to industrial chemicals and materials originate from the consequences of irreversible or progressive damage that can occur to the nervous system. An ATSDR initiated NRC study recommends prioritizing evaluation of new chemicals and materials that are produced in large scale, which are potentially hazardous and pose a risk to the central nervous system (CNS) of individuals in the workforce. In this regard, nanomaterials are receiving immense attention because of their large scale production and $1 trillion market potential over the next decade. Due to their unique physico-chemical properties, nano-sized materials can aerosolize during manufacturing, handling or recycling, and thus inhalation exposure is of major occupational concern. Like nanoparticles, aerosolized chemical agents, fine and ultrafine particulates, including welding fumes and mineral dusts also pose similar occupational risks. While their potential for industrial applications is significant, there is paucity of information regarding their biological actions and adverse neurotoxicological effects.
Laboratory-based animal studies will be conducted to model human exposure conditions to a variety of engineered nanoparticles (MWCNT, TiO2 nanospheres and nanowires) as well as, ultrafine and fine particulates generated at the workplace (welding fumes). Neurotoxicological potential of these materials will be tested in mice (C57BL/6J) or rats (Sprague-Dawley) following pulmonary aspiration, intratracheal instillation or inhalation exposure paradigms. Dose response and time course of neurotoxicity will be characterized. A 3-tier approach containing a battery of molecular and histological screens will be executed to evaluate neurotoxicity. In Tier I, integrity of blood brain barrier (BBB); neuronal ion channel, neurotransmitter and mitochondrial function, as well as, neuroinflammatory and oxidative/cellular stress responses will be evaluated. If molecular changes are observed, Tier II approach will be implemented to assess neuronal damage by histological techniques, including sensitive degeneration stains and immunohistochemical analysis. If neuronal injury is evident, in Tier III we will perform genomic and proteomic analysis to characterize the mode of action and unravel novel markers of neural injury. Simultaneously, blood gene expression profiling will be performed to correlate CNS changes and identify peripheral markers of neuronal damage. In addition, an attempt will be made to corroborate the molecular findings with alterations in neurobehavior and MRI T1 hyperintensity in the brain at time points that precede overt neuropathology. Based on the neurotoxic potential of the materials examined, opportunities to conduct clinical studies to evaluate exposures in worker populations will be explored. The study is designed to integrate a broader approach to neurotoxicological evaluation, including neurobehavioral and neuroimaging studies.
Collaborations with internal (HELD) and external (NIST, WVU, University of Montana, Carnegie Mellon University, Shinshu University, Mitsui & Co., USA) partners have been established for successful accomplishment of the project. This interdisciplinary team has the expertise necessary for delivery of definitive outcomes. Mitsui and Co., USA is the industry partner for the MWCNT toxicity study.
Our preliminary studies with nanoparticles indicate that MWCNT, nanosphere and nanowire TiO2 alter BBB permeability, ion channel and glucose transport function, oxidative/cellular stress responses, and neuroinflammatory changes in mice. Similarly, aerosolized ultrafine and fine welding fume and crystalline silica particles elicited BBB and neuroinflammatory changes, suggesting potential neurological effects.
Engineered nanomaterials (metal oxides and carbon-based nanomaterials), ultrafine and fine particulates (welding fumes) have the potential to aerosolize and thus inhalation or ocular exposure is of major occupational concern. Translocation of nanoparticles to the brain, from either the olfactory system or through systemic circulation, can have far reaching consequences by causing irreversible damage to the nervous system. However, at present there is a paucity of information on the adverse neurotoxicological effects of nano- and fine-size particles manufactured and/or generated at the workplace. To predict and reduce the risk of occupational illnesses, this project will evaluate potential neurological effects following exposure to nano- and fine-sized materials. Neurotoxicological potential of these materials will be evaluated laboratory-based animal studies. By accomplishing the goals set for this project, fundamental neurotoxicological data will be obtained that will help understand the potential exposure hazards posed by nano- and fine-sized particles. This knowledge will provide critical data needed for hazard identification, risk assessment and setting occupational exposure limits.
The long-term goals of this project are to conduct investigations to determine the neurotoxicological risks associated with occupational exposures to industrial materials, with emphasis on engineered nanomaterials, aerosolized ultrafine and fine particles generated by processes such as welding and abrasive blasting, and chemical agents. The specific objectives include:
1. Neurotoxicological evaluation of occupational exposure to industrial materials, with emphasis on engineered nanomaterials.
2. Neurotoxicological evaluation of occupational exposure to welding fume particulates.
3. Near infrared (IR) or magnetic resonance (MR) imaging to detect translocation pathways and localize sites of neuronal damage induced by nanomaterials and welding fume particulates.
4. Molecular profiling to identify and characterize the mode of action of welding fume particulates and to determine novel indicators of neurotoxicity.
5. Evaluating the efficacy of blood gene expression profiling as a non-invasive peripheral marker for detecting welding fume-induced neurotoxic exposures.
With rapid industrialization, increased association of workplace exposure to aerosolized materials with occupational risks and neurological disorders is expected. Today the economic impact of neurological disorders in the U.S. is estimated at $360 billion, with approximately 68 million people affected by nervous system illnesses. Whether occupational exposures are the cause for some of these disorders remains unknown. In this regard, both engineered and workplace generated nanoparticles are receiving immense attention, as there is concern that inhalation of such particles may cause adverse systemic health effects, including neurological deficits. Laboratory-based animal studies will be performed to evaluate neurotoxicity of engineered nanomaterials and welding fume particulates, following pulmonary (aspiration or intratracheal instillation) and/or whole-body inhalation exposure. The proposed project will support Agency goals and the Research to Practice (r2p) initiatives by (1) characterizing adverse neurological effects of nanoparticles, (2) providing critical neurotoxicology data for hazard and risk assessment (3) helping establish exposure limits, safe handling practices and bio-monitoring procedures, which help development of interventions to eliminate or minimize such exposures. Neurotoxicological data will be disseminated to stakeholders' to encourage implementation of effective prevention practices and safe work conditions. Molecular profiling studies will help characterize the mode of action of these materials and identify early indicators of toxicity. Specific markers or a panel of such injury markers identified can be utilized to develop non-invasive tools (biosensors) for detecting similar neurotoxic exposures. Data from molecular analysis may also aid the development of neurotoxicity risk assessment paradigms. Overall, these studies will contribute to hazard identification, risk assessment and development of occupational health and safety recommendations, thereby supporting the NIOSH goal of reducing illness and injury at the workplace.
CON: 40% SG 6 (09PPCONSG6): Reduce welding fume exposures and future related health risks among construction workers by increasing availability and use of welding fume controls and practices for welding tasks.
IG 6.5 (09PPCONIG6.5): Evaluate hazard and exposure assessment research gaps associated with welding fume in construction.
SG12 (09PPCONSG12): Increase understanding of how vulnerable worker groups experience disproportionate risks in construction work and expand the availability and use of effective interventions to reduce injuries and illnesses among these groups.
IG 12.2 (09PPCONIG12.2): Improve our understanding of conditions and risk factors that contribute to the vulnerability of workers and the mechanisms through which vulnerability places workers at increased risk for work-related injury (or illness) in the construction trades, and their longitudinal effects
MNF: 60% SG 5 (09PPMNFSG5): Reduce the number of respiratory conditions and diseases due to exposures in the manufacturing sector.
MNF: SG 9 (09PPMNFSG9): Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing.
CRC: 100% SG 5 (09PPCRCSG5): Reduce the incidence and mortality of other chronic diseases, including, work-related neurologic (cerebrovascular) and renal disease.
NAN: 75% SG 1 (09PPNANSG1): Determine if nanoparticles and nanomaterials pose risks for work-related injuries and illnesses.
EXA: 25% SG 2 (09PPEXASG2): Develop or improve specific methods and tools to assess worker exposures to critical occupational agents or stressors.
IG 2.4 (09PPEXAIG2.4): Develop bio-monitoring methods including biomarkers that are useful for mixed exposures.
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