NORA Manufacturing Sector Strategic Goals
927003J - Occupational-Related Risk Factors and Cardiovascular Disease
Principal Investigator (PI)
Primary Goal Addressed
Secondary Goal Addressed
Attributed to Manufacturing
Cardiovascular diseases, related to atherosclerosis, continue to be the principal cause of death in the United States. The purpose of this laboratory-based research project is to evaluate the effects of occupational exposure to ultrafine and nanosize particulates on development of cardiovascular diseases. Occupational exposure to welding fumes and nanoparticles may induce systemic effects of oxidative stress and inflammation which lead to impaired vascular homeostasis and progression of atherosclerotic processes. The proposed studies will help to identify potential risk factors, biomarkers, and specific targets for prevention and therapeutic intervention of occupational-related cardiovascular diseases. The project will help NIOSH to meet its strategic goals in several sector and cross-sector programs, including constuction, manufacturing, transportation, cardiovascular, respiratory diseases, and nanotechnology related to better define workplace exposures with potential risk for morbidity and mortality.
Human studies on the role of particle exposure in progression of atherosclerosis and related cardiovascular diseases are influenced by numerous factors (e.g., characteristics of the exposure, personal and life style confounders and population size). Understanding of the underlying biological mechanisms of the interaction between particle exposure and atherogenesis can not be achieved without studies in relevant animal models. Recently, we characterized the application of experimental mouse models for studying the role of metals in atherosclerosis. In these studies we were able to support the epidemiological findings linking arsenic exposure and atherosclerosis.
The central hypothesis of our current studies is that long-term exposure to occupational related particles such as welding fumes, inorganic carbon nanomaterials, and diesel emissions induces systemic effects of oxidative stress and inflammation which modify the atherosclerotic processes. To test this hypothesis we will use and characterize specific animal models, particle exposures and methodologies for measuring parameters of oxidation/inflammation as well as of plaque formation and progression. The unique physical characteristics (shape; size; surface area) and the metal constituents of the particles are major predictors for vascular toxicity. Smaller particles have greater deposition in the deep lung, a high surface area-to-mass ratio and prolonged clearance, potentially leading to lung inflammatory responses. The transition metals associated with the particles accelerate the oxidative stress-driven pulmonary inflammation. As a result, inflammatory mediators and oxidants might be released into the circulation leading to impaired endothelial as well as blood cell homeostasis. All stages of atherosclerosis can be modified by oxidative stress and inflammation. The specific aims of the proposal are: 1. To evaluate and characterize the blood and vascular homeostasis in wild type mice exposed via the respiratory route to several well characterized particulates such as welding fumes and carbon nanomaterials; 2.To analyze the effects of these partculate exposures on atheroma formation and progression in mice, genetically predisposed to develop atherosclerosis (ApoE-/-); and 3.To elucidate biomarkers and atherogenic mechanisms involved in particle-induced effects by in vitro and in vivo models. Under aim 3, several mechanistic paradigms will be tested including: A. Particle exposure and vascular mitochondrial dysfunction; B. Particle exposure and impaired endothelial repair mechanisms; C. Particle exposure induces blood cell activation which can predict cardiovascular outcomes; and D. Particle exposure and direct cardiovascular effects through a release of soluble metals and/or small size particles into the circulation.
The proposed studies will help identify the risk of certain workplace particle exposures to affect the cardio-vascular system, will provide mechanistic information for risk assessment and will help to identify specific targets for prevention as well as therapeutic intervention of occupational-related cardiovascular diseases.
• To evaluate the effects of different doses and time courses of respiratory exposure to several types of welding fumes and nanomaterials in development of vascular cell dysfunction.
• To evaluate the effects of different doses and time courses of respiratory exposure to several types of welding fumes and nanomaterials in atheroma formation and progression.
• To analyze different blood parameters (including inflammatory mediators; blood cell gene expression, lipid profiles); these findings can provide potential biomarkers for prediction of particle-mediated cardiovascular outcomes.
• To assess the risk of transport of certain particles or their constituents from the lung into the systemic circulation.
• To characterize the link between the physicochemical properties of the particles and their potential to induce inflammation or oxidation related to cardio-vascular toxicity.
• To evaluate the link between lung inflammation and atherosclerosis.
• To identify particle mediated molecular mechanisms of cardiovascular toxicity which will help for development of new prevention/therapeutic targets of cardiovascular diseases.
• Multiple peer review publications.
• Presentations of national and international scientific meetings.
• NIOSH documents.
• Citations of our findings in scientific publications and documents.
• Implementation of the findings in risk assessment of ultrafine/nanoparticle exposures to improve workers' health
Cardiovascular diseases, the majority of them related to atherosclerosis, continue to be the principal cause of death in the United States as stated in the document Healthy People 2010. Each year in the United States, cardiovascular diseases kill 923,000 people and accounts for 43% of total mortality. Cardiovascular diseases cost the nation approximately 159 billion dollars annually. The BLS estimated that heart attacks were responsible for more deaths than any other occupational diseases (U.S. Bureau of Labor Statistics, 1991). Latter analysis of job-related and occupational data from the Bureau of Labor Statistics' Supplementary Data System (SDS) revealed that circulatory diseases including heart attacks are more significant than any other diseases in contribution to deaths and permanent disabilities of workers.
Hyperlipidemia, hypertension, obesity, diabetes, and cigarette smoking are the common risk factors for atherosclerosis. Increasing number of evidence demonstrates that, in addition to these risk factors, some environmental risk factors may also play a role in development or progression of cardiovascular diseases. For instance, during the past few years many epidemiological and experimental studies have suggested positive associations between particulate matter in air pollution and adverse cardiovascular outcomes. Workers are exposed to particulates in many industries, including welding, mining, construction, or nanotechnologies. Recently, the American Heart Association recognized the need for extensive research on the particulate exposure–induced cardiovascular toxic effects and mechanisms.
This project will evaluate the risk of respiratory exposures to occupational-related particles to induce systemic and vascular effects, prerequisites for atherogenesis and associated cardiovascular diseases. Smaller particles have greater deposition in the deep lung, a high surface area-to-mass ratio and prolonged clearance, potentially leading to lung inflammatory responses. The transition metals associated with the particles accelerate the oxidative stress-driven pulmonary inflammation. As a result, inflammatory mediators and oxidants might be released into the circulation leading to impaired endothelial as well as coagulation homeostasis. All stages of atherosclerosis can be modified by oxidative stress and inflammation. To test this hypothesis we will use well defined animal models, exposures and methodologies that measure parameters of oxidation/inflammation as well as of plaque formation and progression. The specific aims of the proposal are: 1) To evaluate and characterize the blood and vascular homeostasis in mouse models via the respiratory route to several well characterized welding fumes and carbon nanotubes; 2) To analyze the effects of welding fume and carbon nanotube exposure on atheroma formation and progression in mice, genetically predisposed to develop disease and 3) To elucidate putative biomarkers and atherogenic mechanisms involved in particle-induced effects by in vitro and in vivo models.
The findings of the project will help to identify unknown occupational-related risk factors for cardiovascular diseases. Furthermore, they will help in the development of new protection strategies for reducing the cardiovascular diseases in workers. This research will also help for establishment of optimal safety regulations of ultrafine/nanosized particulate exposures. The project will help in identification of new biomarkers of occupational exposure with potential risk for adverse cradiovacular effects. The findings will facilitate the intramural, extramural research and epidemiological studies on cardiovascular diseases and mortality.
Construction sector (25%):
STRATEGIC GOAL 6.0 – 09PPCONSG6 Reduce welding fume exposures and future related health risks among construction workers by increasing the availability and use of welding fume controls and practices for welding tasks
Performance Measure – A performance measure cannot be set for this strategic goal until better baseline information can be obtained and analyzed. SG 6.0 - IG 6.5 "Improve understanding of dose-response relationships in welding fume toxicity and develop new approaches for reducing toxic metal exposures from welding fume"
Intermediate Goal 6.5 – 09PPCONIG6.5 Evaluate hazard and exposure assessment research gaps associated with welding fume in construction
Performance Measure – Support at least 3 research projects to address hazard and exposure gaps and provide findings to construction researchers and stakeholders
Research Goal 6.5.1 – 09PPCONAOG6.5.1 Health hazard testing component - Support research to improve understanding of health effects and field exposures to welding fumes – both for special contaminants of concern and for contaminant mixtures associated with the ten most common types of welding combinations. Basic research is needed on the health effects associated with the mixed exposures resulting from welding operations.
Manufacturing Sector (50%):
Strategic Goal 5 (09PPMNFSG5): Reduce the number of respiratory conditions and diseases due to exposures in the manufacturing sector.
Strategic Goal 9 (09PPMNFSG9): Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing.
Transportation, Warehousing, and Utilities (25%):
Strategic Goal 3 (09PPTWUSG3): By 2016, improve health and reduce premature mortality among TWU workers through workplace programs and practices that (1) enable workers to engage in healthy behaviors, (2) reduce work-related physiological and psychological stressors, and (3) improve healthcare utilization.
Cancer, Reproductive, Cardiovascular and Neurologic Diseases Cross Sector (50%) Strategic Goal 4 (09PPCRCSG4): Reduce the incidence and mortality of work-related cardiovascular disease
Intermediate Goal 4.1 (09PPCRCIG4.1): Conduct research to better define the contribution of workplace exposures and workplace factors (e.g., levels of activity or inactivity) to the overall incidence of and mortality from cardiovascular disease (CVD).
Respiratory Diseases Cross Sector (50%)
Strategic Goal 5 (09PPRDRSG5):
Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials.
Intermediate Goal (09PPRDRIG5.1): determine the potential respiratory toxicities of nanomaterials.
Activity/Output Goal (09PPRDRAOG5.1.1): perform basic in vitro and in vivo toxicology studies to evaluate for respiratory toxicity of nanoparticles and, if present, to characterize nanoparticle characteristics and mechanisms of action underlying toxic effects.
Nanotechnology coordinated emphasis areas (50%)
Strategic Goal 1 (09PPNANSG1). Determine if nanoparticles and nanomaterials pose risks for work-related injuries and illnesses.
Intermediate Goal 2.1 (09PPNANIG2.1) Key factors and mechanisms. Systematically investigate the physical and chemical properties of particles that influence their toxicity (e.g., size, shape, surface area, solubility, chemical properties, and trace components). Evaluate acute and chronic effects in the lungs and in other organ systems and tissues. Determine rates of clearance of nanoparticles after pulmonary exposure and translocation to systemic organs; characterize systemic effects.
Intermediate Goal 2.2 (09PPNANIG2.2) Predictive models for toxicity. Integrate mechanistic models (including animal models and in vitro screening tests) for assessing the potential toxicity of new nanomaterials and provide a basis for developing predictive algorithms for structure/function relationships and comparative toxicity analyses for risk assessment. Evaluate the relationship between in vitro and in vivo responses, the relevance of instillation or aspiration exposure to inhalation, and the relevance of animal studies to human response.
JUSTIFICATION: Inhalation exposure to dust is associated with increased risk to pulmonary and cardiovascular diseases. This exposure can occur during construction work. Exposure to engineered nanomaterials (NM), new materials, can occur during their manufacturing and application. Risks for cardiovascular toxicity are unknown, but based on the air pollution data are possible.