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Cytotoxicity and solubility of beryllium particles.

Breysse-PN; Stefaniak-AB; Scripsick-RC; Hoover-MD; Valdez-YE
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R03-OH-007447, 2004 Nov; :1-29
The long-term goal of this research is to develop more protective industrial hygiene metrics of exposure that are related to bioavailability, and therefore, potential risk of immune-mediated diseases caused by exposure to metals. We chose chronic beryllium disease (CBD) as a model for this research because it is a potentially fatal cell-mediated immune disease of the lung with no known cure that continues to be diagnosed among workers exposed to beryllium and former workers no longer exposed to beryllium. CBD is associated with exposure to beryllium containing particles; however, at the cellular level a dissolved beryllium species is the hypothesized input to the immune reaction that drives development of CBD. As beryllium containing particles dissolve in phagocytic lung cells, a fraction of the dissolve material may be consumed in the formation of the beryllium antigen, which is hypothesized to cause CBD. Little is known about the physicochemical properties or dissolution behavior of respirable beryllium aerosols, suggesting that the relationship between exposure to beryllium and dose is not well understood. Dissolution (conversion from particle to a dissolved species) is a physicochemical process. Physicochemical properties of four materials were characterized utilizing a suite of analytical techniques: finished product beryllium metal powder and beryllium oxide powder, and particles sampled from manufacturing processes during production of beryllium oxide and copper-beryllium alloy. All study materials are associated with elevated prevalence of CBD. Characterization of study materials included aerodynamic size-separation and microscopy to understand size and morphology, x-ray diffraction (XRD) to determine crystalline chemical composition, and surface area analysis to determine specific surface area (SSA). Lacking a model of the acidic liquid environment of the pulmonary alveolar macrophage phagolyososome, the hypothesized site of beryllium dissolution, a solvent model termed phagolysosomal simulant fluid (PSF) was refined and characterized. Efforts to characterize the solvent included comparison of beryllium dissolution in PSF to dissolution in the J774A.l murine monocytemacrophage cell line. No difference in beryllium dissolution was observed in PSF compared to the J774A.l cell line, thus PSF was used to determine the chemical dissolution rate constant (k), having units of g/(cm2 day), for each material. The k value is a constant unique to a given chemical form of beryllium, and permits intercomparison of dissolution rate data. Results indicated that physicochemical properties, and in turn, values of k, differed among the study materials. The ranking of materials by solubility (from greatest to least) was beryllium metal powder > beryllium oxide powder approximately the same as beryllium oxide particles sampled from a production process. For the copper-beryllium particles studied, measured SSA for the entire sample did not govern beryllium dissolution from the beryllium oxide component of the particles. Additional studies of this material showed that dissolution did not vary with measured SSA of the entire sample as expected from dissolution theory. Using k determined for beryllium oxide, the effective beryllium oxide SSA was calculated for the copper-beryllium material using a technique developed as part of this project. To account for measured dissolution, the SSA of the beryllium oxide component of the copper-beryllium particles must be several orders of magnitude higher than the SSA determined for the total particle sample. Research performed as part of this project improved understanding of how physicochemical properties of beryllium aerosols relate to solubility by using a solvent of phagolysosomal fluid. An understanding of beryllium particle dissolution is important because the rate of dissolved beryllium production may be the rate limiting step in the activation of the CBD immune response. Data collected indicate that k values of beryllium materials with capacity to cause CBD may vary by an order of magnitude or more. Thus, an improved approach for regulating exposure might categorize chemical forms of beryllium according to solubility characteristics and SSA, with those materials producing dissolved beryllium at a rate sufficient for activation and maintenance of the CBD immune response posing the highest risk.
Cytotoxicity; Cytotoxins; Cytotoxic-effects; Beryllium-compounds; Metals; Occupational-exposure; Industrial-hygiene; Risk-analysis; Risk-factors; Lung-cells; Aerosols; Models; Solvents
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Final Grant Report
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NIOSH Division
Priority Area
Disease and Injury: Asthma and Chronic Obstructive Pulmonary Disease
Source Name
National Institute for Occupational Safety and Health
Performing Organization
Johns Hopkins University, Baltimore, Maryland