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workers, building, architect

NORA Manufacturing Sector Strategic Goals

927Z1KD - Computational Studies of Mineral Dust Properties

Start Date: 10/1/2005
End Date: 9/30/2009

Principal Investigator (PI)
Name: James Snyder
Phone: 304-285-6364
Organization: NIOSH
Sub-Unit: HELD
Funded By: NIOSH

Primary Goal Addressed

Secondary Goal Addressed


Attributed to Manufacturing


Project Description

Short Summary

Workers in construction and manufacturing with long-term exposures to respirable quartz-contaminated dusts are at high risk of developing pulmonary diseases such as silicosis, coal workers' pneumoconiosis and lung cancer. This project will establish the molecular specificity of mineral dusts interactions with biomaterials of the pulmonary airways by studying adsorption of a pulmonary surfactant molecule on crystalline surfaces of silica quartz and kaolinite (aluminosilicate). Selective removal of this protective coating from mineral particles causes restoration of the cytotoxicity of respirable silica dusts. Using computational methods to model these interactions, we hope to help explain why quartz silica causes silicosis while aluminosilicate (kaolinite) does not. This fundamental knowledge will advance our understanding of the properties of crystalline silica that contribute to its pathogenicity.


In vitro short-term bioassays studies have revealed that both quartz and kaolin dusts have comparable membranolytic potential and cytotoxic potential on a total surface area basis. Suppression of the hemolytic activity results after treatment of the dusts with dipalmitoylphosphatidylcholine (DPPC), a common component of the lung pulmonary surfactant (LPS). DPPC adsorption onto the dust particle surfaces completely eliminates the cytotoxic activities of the dusts immediately after incubation with DPPC. However, the membranolytic activity of both dusts is partly to fully restored following digestion of DPPC with phospholipase A2 (PLA2), an enzyme normally found associated with cellular plasma membrane and lysozymes. DPPC surfactant is lost more readily on quartz than on kaolinite, with concomitantly more rapid restoration of mineral surface hemolytic activity for quartz.

NMR studies on the interaction of DPPC with silica particles indicate that the phosphate group of DPPC is coordinated to surface hydroxyls. More recent NMR results suggest that the (positively charged) choline unit of DPPC is immobile on silica surfaces but is unrestricted toward motion on kaolinite. The orientation of DPPC on the surface may influence the rate of PLA2 enzyme activity and therefore bio-reactivity.

Experimental investigations of the surface chemistry of occupational dust particles need to be complemented by computational studies. The computational goal is to deduce adsorption properties of LPS on surfaces mineral crystals by means of molecular modeling. Such studies could predict the preferred conformation of LPS on the surface. Preliminary results from gas-phase ab initio calculations have provided information on the nature of the bonding and geometry within these complexes. ab initio cluster calculations have been performed on different sized silica clusters to characterize surface sites. These studies will be extended to include a DPPC molecule in a silica or aluminosilicate complex, as part of the initial phase of this computational study. Since a potentially large number of conformations may be available for organic molecules such as DPPC, molecular dynamics is a suitable tool for generating a starting conformation for a gas phase ab initio calculation. Ultimately, it will be necessary to combine a crystal surface (slab) and liquid aqueous phase with DPPC in a single molecular dynamics simulation.

The proposed project consists of several stages. ab initio calculation of singular surfaces of crystalline silica and kaolinite and density functional methods calculations will be used for simulations involving the quartz slab+DPPC system. Calculations on reconstructed pristine and hydrolyzed surfaces of quartz have predicted the relative importance of single silanol (= Si-OH) and double silanol [geminol silandiol, >Si-(OH)2 ] groups on these surfaces. Results, based on interaction of DPPC with a single surface silanol group may differ when interaction with double surface silanol groups are involved. A set of molecular dynamics force field parameters suitable for SiO2 surfaces has recently been derived and tested. These parameters will allow molecular dynamics calculations involving silica clusters and the silica slab+aqueous DPPC system. Ionization states (pKa's) of surface silanol groups are important for understanding physiosorption. Deprotonation energies of silanol groups in silica clusters have been calculated which provide some qualitative information such as the relationship of acidity to degree of silica polymerization. More accurate results can be obtained using continuum dielectric models which include (implicitly) the solvent. Future studies would focus on the catalytic mechanism of phospholipase A2 in the presence of silica and aluminosilicate.


The major objective of the project is to model computationally the interactions of the DPPC component of the lung pulmonary surfactant with silica and aluminosilicate. The results of this project will contribute to fundamental knowledge of the mechanism of lung pulmonary fibrosis and silicosis and potential ways of preventing and treating these chronic occupational diseases.

Mission Relevance

Workers with long-term exposures to respirable quartz-contaminated dusts are at high risk of developing pulmonary diseases such as silicosis, coal workers' pneumoconiosis and lung cancer. According to the National Surveillance System for Pneumoconiosis Mortality in 1997 there were 2928 pneumoconiosis deaths among persons of age 15 or older. The NIOSH worker health chart book indicates approximately 85% of these workers were in manufacturing, 5% in mining, and 10% in construction. The exact molecular mechanism of quartz cytotoxicity has remained elusive primarily due to the extreme variability in surface properties among silica dusts arising from different sources. This variability relates both to the geological origin of the source rock, and to the processes taking place when the dust is generated, stored, aerosolized and inhaled.

Upon deposition in the lung, respirable dust particles may interact with biological fluids and materials, including surfactant components of the pulmonary bronchiolar -alveolar surface. As a result, knowledge about the adsorption processes on silica surfaces plays a crucial role in understanding the origin of the resulting pathogenicity. A question that remains unanswered is why exposures to crystalline silica cause silicosis, while silica in the form of aluminosilicates (clays, kaolin) or amorphous silica (glass) does not. It is known that lung pulmonary surfactant (LPS) may be an efficient natural prophylactic against the otherwise prompt action of many types of cytotoxic dust. Presumably, the LPS molecules adsorb on the surface of respired particles forming a protective coating that suppresses toxicity of quartz and clay particles. Our working hypothesis suggests that the differences in enzymatic digestion rates of surfactant removal from the different mineral particle surfaces are due to the different adsorption properties of LPS on pure crystalline silica and aluminosilicates. We will use computational simulation methods to model the interaction of LPS with different forms of silica. Examination of different surfaces of crystalline silica and aluminosilicates and their interactions with LPS can provide valuable insight on the nature of LPS adsorption and protective action. The present proposal is motivated by priority #20-4 of the CDC Healthy People 2010 program and OSHA priority guideline #14, silica (crystalline).

Results will address:


Construction (25%) Research Goal 09PPCONAOG5.5.1 Reactive species hazard component - Support research to improve understanding of health effects and field exposures associated with mixed exposures to silica particulates co-generated with metal exposures

Manufacturing Sector (75%) Strategic Goal 5 (09PPMNFSG5): Reduce the number of respiratory conditions and diseases due to exposures in the manufacturing sector from inhalation exposures to manufacturing materials

Cross Sectors

Immune and Dermal (50%) Immune Strategic Goal 1 (09PPIMUSG1): Contribute to the reduction of immune abnormalities associated with workplace exposures, specifically Intermediate Goal 1.1 (09PPIMUIG1.1): Contribute to the advancement of knowledge regarding the impact of occupational exposures to chemicals or biological agents on normal immune function and Activity/output goal 1.1.3 (09PPIMUAOG1.1.3) Evaluate the immunotoxicity caused by exposure to certain occupational chemicals or allergen and Activity/output goal 1.1.4 (09PPIMUAOG1.1.4) Hazard identification of occupational chemicals/allergens.
Respiratory Disease (50%) Strategic Goal 1 (09PPRDRSG1): Prevent and reduce work-related airways diseases specifically Intermediate Goal (09PPRDRIG1.1): prevent and reduce the full range of work-related asthma (WRA), including work-exacerbated asthma; occupational asthma; and irritant-induced asthma. Strategic Goal 2 (09PPRDRSG2):
Prevent and reduce work-related interstitial lung diseases; Activity/Output Goal (09PPRDRAOG2.2.3): develop, improve and validate sampling and analytical methods for assessing exposures to silica.
Strategic Goal 4 (09PPRDRSG4): Prevent and reduce work-related respiratory malignancies; Activity/Output Goal (09PPRDRAOG4.1.4): Elucidate mechanisms of silica-induced lung cancer and reduce silica exposures (exposure reduction is discussed in the interstitial lung diseases section).

Other Cross Sectors
Exposure Assessment Emphasis area (100%) Strategic Goal 2 (09PPEXASG2): Develop or improve specific methods and tools to assess worker exposures to critical occupational agents and stressors specifically Intermediate Goal 2.4 (09PPEXAIG2.4): Develop biomonitoring methods including biomarkers that are useful for mixed exposures and Activity/Output 2.4.1 (09PPEXAAOG2.4.1): Development of new biomonitoring methods.