NORA Manufacturing Sector Strategic Goals
927Z1LG - Nanoparticles: Lung Dosimetry and Risk AssessmentStart Date: 10/1/2005
End Date: 9/30/2012
Principal Investigator (PI)Name: Eileen Kuempel
Funded By: NIOSH
Primary Goal Addressed5.0
Secondary Goals Addressed6.0, 9.0
Attributed to Manufacturing
The purposes of this project are: (1) to update and extend the current rat and human lung dosimetry models to account for size-specific differences in the clearance and translocation of inhaled particles, including the role of particle surface area dose; (2) to analyze dose-response relationships in animals and extrapolate to humans; and (3) to predict airborne exposure concentrations in workers that are not expected to cause adverse lung responses, even if workers are exposed to such levels for a full working lifetime. This project will utilize experimental data to be generated in a NIOSH/HELD companion project, as well as data from previously published studies. The long-term goal is to assess the health risks of occupational exposure to nanoparticles and to estimate safe exposure levels.
Epidemiology studies are not available for new engineered nanoparticles. Therefore, toxicology studies are used to predict health risks in workers exposed to nanoparticles. Rodent studies provide evidence that particle surface area dose is a better predictor of toxic response than is mass dose of the same material when the particle sizes differ. An hypothesis of this project is that particle surface area dose elicits an equivalent response (initiating the inflammatory cytokine IL-8 or MIP-2) per epithelial cell surface area both in vitro and in vivo. If this is confirmed, it suggests a biological mechanism for the greater toxicity of a given mass of ultrafine compared to other respirable particle sizes with lower surface area dose. Existing lung dosimetry models in humans and rats may need to be revised to include particle surface area-dependent clearance rate coefficients. In addition, the rat lung dosimetry model is being developed further to include translocation of nanoparticles beyond the lungs, as observed in rodent studies. The revised rat model will be calibrated using in vivo inhalation data of ultrafine and fine titanium dioxide exposure in rats (from a companion project in NIOSH/HELD), as well as data from a previous NIOSH inhalation study of quartz exposure in rats. This is a collaborative project using experimental data (to be generated at NIOSH), as well as extension of previous lung dosimetry modeling at NIOSH in collaboration with external partners. This project will provide a quantitative comparison of particle dose and toxicity using several particle types (titanium dioxide, carbon black, quartz) and size fractions (ultrafine, fine). NIOSH/HELD dose-response data for nanoparticles (e.g. carbon nanotubes) will be used for risk assessment. These data will be extrapolated to humans, and a human lung dosimetry model will be used to estimate working lifetime exposure levels that are not expected to cause adverse pulmonary responses, including inflammation, which may lead to disease development.
This project is expected to take three years to complete, including the time required to develop an extended exposure-dose-response model in rats, validate that model using data generated from the NIOSH/HELD companion studies, and extrapolate the model to humans. Dissemination of the research findings is expected to take another year, for a total of four years. The dosimetry model development will be performed in collaboration with external partners. One of these collaborations with an external partner involves modifying their publicly-available modeling software on particle deposition in rat and human lungs to allow integration of the deposition, clearance, and translocation models. It is anticipated that this project will result in at least two peer-reviewed publications, and may provide a basis for developing NIOSH recommendations on exposure to nanoparticles in the workplace.
The long-term goal of this project is to assess the health risks of occupational exposure to nanoparticles and to estimate safe exposure levels. The specific objectives are to:
1. Evaluate dose-response of inhaled particles by size and type in existing studies
2. Evaluate dose-response using new in vitro and in vivo data (from NIOSH/HELD)
3. Revise and extend current rat lung dosimetry models to include particle size-specific
clearance and translocation
4. Extrapolate the validated rat models to humans
5. Perform quantitative risk assessment for occupational exposure to nanoparticles
The achievement of these goals and objectives will be demonstrated by publication of the results in the peer-reviewed scientific literature.
Rodent chronic bioassay data are frequently used for assessing risk in humans, especially when adequate human exposure-response data are not available. For nanoparticles, human exposure-response data are very limited, and thus rodent data are needed to predict disease risks in workers and exposure levels that would not be expected to cause adverse health effects. Recent studies on deposition of ultrafine particles in the respiratory tract will be used to improve estimation of deposited dose, and data from a companion project in NIOSH/HELD will be used to revise existing lung models to describe the disposition of and response to nanoparticles in the lungs, including evaluation of the particle surface area dose metric for various types of particles. Current scientific studies indicate that nanoparticles may contribute to the development and/or exacerbation of lung and cardiovascular diseases. Yet, human data are limited on the retention of nanoparticles in the lungs and the doses associated with adverse responses including inflammation and disease. Furthermore, studies in rodents have shown that inhaled nanoparticles may translocate to other organs in the body, including the brain, but the implications for humans are unknown. This project will help fill these gaps by quantitatively describing the exposure, dose, and response relationships in rats and extrapolating these results to humans using biologically-relevant extrapolation. The results of this project may be used to develop NIOSH recommendations on occupational exposures to nanoparticles. This project contributes to the following sectors: Manufacturing (50%) – Strategic Goal 5: Reduce the number of respiratory conditions and diseases due to exposures in the manufacturing sector; Strategic Goal 6: Reduce the prevalence of cancer due to exposures in the manufacturing sector; and Strategic Goal 9: Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing. Transportation, Warehousing, and Utilities (50%) – Strategic Goal 4: By 2016, prevent and reduce chemical, biological and physical occupational hazards and exposures resulting in a reduction of occupational injuries, illnesses, and fatalities in the TWU sector. This project also contributes to these Cross-Sector Programs: Nanotechnology (50%): Strategic Goal 1: Determine if nanoparticles and nanomaterials pose risks for work-related injuries and illnesses. Respiratory Diseases (50%) -- Strategic Goal 1: Prevent and reduce work-related airways diseases; Strategic Goal 2: Prevent and reduce work-related interstitial lung diseases; Strategic Goal 4: Prevent and reduce work-related respiratory malignancies; and Strategic Goal 5: Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials. Cancer, Reproductive, and Cardiovascular Diseases (25%) -- Strategic Goal 1: Reduce the incidence of work-related cancer.
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