- © 2001 American Mineralogist
Dissolution rates of a well-characterized sample of powdered talc were measured in solvents that mimic fluids found in the human lung. These experiments found that talc dissolution rates were the same for pH controlled aqueous solvents, phosphate buffered saline solution, and modified Gamble’s solutions. Variation of solvent chemistry, including the addition of organic chelators and proteins at intercellular fluid concentrations, does not markedly affect the measured dissolution rate of talc at 37 °C. The data further indicate that the dissolution mechanism for talc in aqueous solutions is independent of pH over the range of 2 to 8. The dissolution rate at 37 °C, determined by measuring the silicon release rate per unit surface area of talc in a mixed-flow reactor system, is 1.4 (±1.0) × 10−11 mol Si/m2·s. Application of a geometric shrinking particle model using this dissolution rate results in an estimated lifetime (upper limit) of approximately 8 years for a 1 μm talc particle under pulmonary conditions. Talc dissolves considerably faster than quartz, but slower than chrysotile and olivine in the body. These data can be used to place constraints on the role of particle dissolution in the disease models associated with airborne respirable mineral particles.
The recent focus on the behavior and control of inhaled mineral particles by the medical and regulatory communities presents geochemists an opportunity to extend principles traditionally used in characterizing the dissolution of minerals into the new field of biologically based dissolution studies. Adaptation of traditional mineral dissolution rate studies to mimic the physical and chemical conditions encountered in the lungs allows geochemists to estimate mineral biodurability in the lung through calculation of residence times based on the dissolution clearance mechanism. Mineral dusts are pervasive in our environment and we are continuously exposed to them on a daily basis. Mechanical and chemical weathering processes produce readily suspended dusts, which may then be taken up into the lungs (Klein 1993). The respiratory exposure to specific mineral dusts has long been known to cause adverse heath effects, including scarring and thickening of the tissues of the lung, and the development of cancer (Kane 1993). For instance, exposures to airborne asbestos minerals are known to cause mesothelioma, lung cancer, other cancers, and other lung diseases, such as asbestosis. Similarly, exposure to elevated concentrations of quartz can produce silicosis, and occupational exposures to high concentrations of relatively “pure” airborne talc dusts have been linked to talcosis, a relatively benign lung pneumoconiosis (Gamble 1986). The effects of exposure are considered severe enough that exposures to dusts, including mineral dusts, are regulated in the workplace. The United States Environmental Protection Agency also regulates fine airborne particulate matter, which includes mineral dusts, through Clean Air Act regulations (USEPA 1997).
Silicates are used extensively in industry. Olivine is processed as a source of magnesium and olivine sands are used in high temperature foundry operations and as a substitute for quartz sand. The number of workers exposed regularly to olivine is, however, relatively small. There have been no reports of occupational respiratory disease associated with exposure to olivine, although there is no epidemiological data describing the effects of exposure (Gamble 1986). Chrysotile asbestos is considered a human carcinogen, and regulated as such in the U.S. workplace (Stayner et al. 1996; USDOL 1994). Historically, chrysotile was used extensively in the United States. Chrysotile was incorporated into a wide range of commercial products due to its thermal stability and tensile strength, including thermal systems insulation, vehicle brake linings, transite siding, vinyl floor tile, and decorative or thermal architectural finishes. Exposures to chrysotile were associated with the processing of the mineral and the manufacturing and application of asbestos containing products. Exposures to crystalline silica (mostly quartz) are widespread, both from the workplace and the environment. Exposure to crystalline silica in the workplace has been linked to silicosis, a progressive pneumoconiosis. Debate on the role of crystalline silica in the development of cancer in exposed populations continues, but it is unlikely that significant cancer risk is associated with exposures to crystalline silica at current occupational exposure control limits (McDonald 1995). Talc is used extensively in industry and is incorporated into a wide range of products including paints, coatings, cosmetics, pharmaceuticals, and as coatings on paper. As a result, the cohort of potentially exposed workers is much larger than the population of olivine-exposed workers. This use results in exposures to a large segment of the population in both the work place and in the home. Talc is so widely used that exposures extend from infancy through old age and this results in a large potential for exposure to the mineral through dermal and airborne routes. Chronic exposures to high concentrations of talc have been associated with development of talcosis, a benign pneumoconiosis (Gamble 1986). Confounding coincident exposures to crystalline silica and amphibole asbestos have been noted.
The physical characteristics of the inhaled particles determine where particles will deposit in the lung. Particle dimensions and surface properties, as well as the velocity of the air stream in the respiratory system determine the depth to which particles may penetrate the lung. In general, particles with aerodynamic diameters greater than approximately 10 μm impact in the upper reaches of the respiratory tract and are rapidly moved up the bronchioles by specially adapted ciliated cells (the mucocilliary escalator) which sweep the particles toward the throat. These particles are then cleared and expectorated or swallowed. Particles with equivalent diameters of approximately 1–2 μm are most likely to penetrate deeply to the alveolar regions of the lung (Glenn and Craft 1986). The body’s natural clearance processes are not as efficient in the deep lung, and these particles may persist. These very fine particles are of the most concern because their presence in these tissues can result in scarring of the alveolar walls which results in reduction of the ability to exchange gasses across the alveolar membrane.
One factor controlling the tendency of a given particle to cause a disease must be related, in part, to the residence time of the particle in the pulmonary environment. Mineral dusts are cleared from the lung by several different mechanisms, including exhalation of suspended particles, sequestering of particles by specialized cells (macrophages), relocation via the mucocilliary escalator and via the lymphatic system, in situ dissolution, or a combination of these mechanisms (Lehnert 1992). One of the factors controlling the residence time is a particle’s biodurability, or its resistance to chemical dissolution in the body. We wish to distinguish the term “biodurability” from “biopersistence” which we define as a particle’s total resistance to all clearance mechanisms. The biodurability of mineral dusts may then be a factor in the tendency for a dust exposure to result in disease. However, to describe adequately the dissolution behavior of minerals in the human lung, it seems reasonable that the solvent solutions must reflect the biochemical composition of the lung fluids. The presence of certain biological compounds, including organic chelators such as sodium citrate has been shown to increase the dissolution rate of cations from minerals (Lund and Aust 1990; Werner et al. 1995).
We used a mixed flow reactor method modified to simulate lung conditions. Experiments were conducted at a fixed temperature of 37 °C. Our preliminary, unpublished method development work indicated that the dissolution rate was independent of pH over a pH range of 2–8 so that precise buffering of the reactor to a physiological pH of 7.4–7.5 was unnecessary. Nevertheless, several runs were buffered at a pH of approximately 7.5, using a phosphate-buffered saline solution. The modified Gamble’s solutions were buffered to a pH of approximately 7.8.
Five kilograms of Fisher Scientific Talcum (Lot no. 920194) were obtained for the experiments and used as received from the manufacturer. A sample of the talc prepared following Asbestos Hazard Emergency Response Act (AHERA) methods (40 CFR Part 763, Appendix A to Subpart E) was analyzed using transmission electron microscopy (TEM). TEM analysis was performed at magnifications of 15 000–20 000× on a Hitachi 600 AB TEM operated at an accelerating voltage of 100 kV. TEM observation of the sample showed that the material was relatively homogeneous in composition and consisted predominantly of talc (>99%). Trace (<1%) quantities of quartz, and an iron-magnesium bearing aluminosilicate were observed. Particle size distribution data reported by the manufacturer for the product are in Table 1⇓.
Surface area analysis
The specific surface area of the talc was measured using a Quantachrome Surface Area Analyzer following the method of Brunauer et al. (1938). Nitrogen was used as the adsorbate gas. The samples were outgassed at 125 °C under a vacuum for approximately 2 hours prior to analysis. The talc used for the experiments had a specific surface area of 6.01 m2/g.
A series of experiments were performed in solvents of increasing physiological relevance. First, the dissolution rate of talc in deionized water adjusted to pH values of 2, 4, and 7.4 using hydrochloric acid or sodium hydroxide was measured. Then the dissolution rates were measured with a phosphate buffered saline solution with a pH fixed at approximately 7.4. Finally, the dissolution rate of talc was measured in two types of “Gamble’s” solutions. One solution was prepared following the formulation of Scholze and Conradt (1987). An additional solution was based on this same composition but included protein in concentrations comparable to those found in the intercellular fluid description of Gamble (1942). Ova albumen was chosen as the protein surrogate since albumen is the most abundant protein in serum plasma (Lentner 1984). The compositions of all solutions used in our experiments are listed in Table 2⇓.
Mixed flow reactor method
Measurements of dissolution rates of talc at 37 °C were performed using a mixed flow reactor following procedures modified from Rimstidt and Newcomb (1993). The experimental system (Fig. 1⇓) includes a 125 mL reaction vessel constructed of acrylic plastic. A fresh 0.2 μm syringe filter was embedded in the effluent port of the reactor prior to each experiment. The sample was agitated using a bar magnet rotated using an overhead magnetic stirrer. Agitation of the high-viscosity protein-rich experiments was accomplished using a wrist-action shaker because the stir bar was unable to keep the talc suspended in the reactor using an overhead stirrer. At the beginning of each experiment, a known weight of solid material (usually 5.00 grams) was loaded into the reactor. Solvent solutions were pumped through the system using a peristaltic pump at flow rates ranging from 0.5 to 1 mL/min. The flow rate was determined at several times through the individual experimental runs by measuring the time required to collect a known volume of effluent. Flow rates of protein rich solutions were lower due to the higher viscosity, and averaged approximately 0.2 mL/min. The pH data were collected at defined times (typically every 15 minutes) using a serial printer interfaced to an in-line Beckman phi 72 pH meter equipped with a Beckman no. 39537 electrode.
After the system reached steady state, as indicated by a constant effluent pH, 30 mL of effluent were collected, usually sometime after two hours of run time. Most experiments were run for longer periods of time. Sample collection times ranged from 95–2466 minutes after the start of the experiment, (Table 3⇓). The effluent was collected into acid-washed, triply (deionized water) rinsed 30 mL Nalgene bottles. The pH and the flow rate of the effluent were recorded at the time of sample collection. All samples were acidified with 1 mL of nitric acid. Stored samples were refrigerated prior to analysis.
Replicate experiments were performed for each solvent, and samples were collected at different times through each experiment. Each sample number denotes a single experimental run. Samples collected through time in a given experiment are designated by a separate letter. The time in minutes from the start of each experimental run is included with the analytical results (Table 3⇑). Several experiments were conducted at a fluid pH of 4 using talc solids recovered and dried from earlier runs. These are indicated by experiments with starting weights less than 5 grams. The 41128 series experiments were conducted on the talc recovered from the 41123 experimental run; the 41130 experiments were conducted on the 41125 series talc.
Silica and magnesium analysis
The silica and magnesium concentrations of the samples were determined using Inductively Coupled Plasma (ICP) analyses. Silica concentrations were measured on a Thermo Jarrel Ash Inductively Coupled Argon Plasma (ICAP) spectrophotometer by integration of the Si 251.611 nm peak. Magnesium concentrations were measured on a ARL/Fisons 3410 Sequential Inductively Coupled Plasma spectrophotometer in vacuum by integration of the 279.079 nm peak. Concentration measurements were referenced to standard solutions prepared from a 1000 ppm Fisher Scientific Si and Mg reference standards. The analytical limit of detection was 0.078 ppm and the relative standard deviation was 3.9% for Si. The analytical limit of detection was 0.045 ppv and the relative standard deviation was 1.1% for the Mg analyses. The protein-free samples were analyzed without dilution. Protein was precipitated from albumen-containing samples using nitric acid. These samples were centrifuged at 5000 g, and then filtered through Whatman no. 2 qualitative filter paper. The recovered supernatant was aspirated directly into the ICP for analysis. Solvent blanks did not contain detectable concentrations of silica. Magnesium concentrations were measured and are reported (Table 3⇑) for all experiments except those performed with Gamble’s solution. The high background concentration of magnesium in the Gamble’s solution was far in excess of the contribution from the dissolution from talc.
The measured silica concentration and the pH of the solution at the time of collection along with the type of experiment, weight of solids, and measured flow rate for each sample, are given in Table 3⇑. A normalized rate constant, k (mol Si/m2 s), was calculated for each sample using the Si concentration, reactor flow rate, sample weight, and the sample specific surface area using:
The results (Table 3⇑) are grouped by solvent type. Rate constants plotted against the pH of the sample (Fig. 2⇓) indicate the average rate of silica release from talc is 1.4 (± 1.0) × 10−11 mol Si/m2 s (n = 49, 1σ error).
Dissolution studies of magnesium silicates have been performed under a range of conditions, yet few have been designed to measure dissolution behavior under physiological conditions. Lin and Clemency (1981) studied the dissolution kinetics of a suite of magnesium silicates, including talc, at room temperature and pressure using a batch reactor. Talc dissolved incongruently in the experiments. Incongruent dissolution of a suite of magnesium silicates (serpentine, forsterite, and enstatite) was also noted by Luce et al. (1972). Hume and Rimstidt (1992) measured the dissolution rate of chrysotile at 37 °C, and determined that a 1 μm fiber would have an expected lifetime of 9 months in the lung, based on a silica release rate of approximately 6 × 10−10 mol Si/m2 s from a shrinking cylinder model.
Gamble (1942) presented a text in which the compositions of physiological fluids were described. This work has served as a basis for a number of experimental derivations for human intercellular fluid, including the experimental solvents used by Scholze and Conradt (1987), and the solutions of Kanapilly et al. (1973). Experimental derivations of fluids based on Gamble’s description have typically included protein free solutions mimicking anionic and cationic compositions of the intercellular or serous fluids.
The silica dissolution rate measured in this study can be used to determine the dissolution rate of talc. Lin and Clemency (1981) indicate the congruent dissolution reaction for talc is:
However, our experiments, as well as those of Lin and Clemency (1981) showed talc dissolves incongruently so that the rate of release of magnesium always exceeds the release rate of silica. This results in the formation of a silica-rich surface on the mineral grains. Therefore, the rate-limiting step in the destruction of the talc particles is the release of silica. The release rate of silica from the talc surface is independent of pH over a pH range of 2–8 (Fig. 2⇑). This is reasonable because the silica dissolution reaction does not consume or produce H+, because:
Furthermore, the rate of dissolution is independent of the solvent chemistry (i.e., pH, buffering capacity, addition of chelators, and addition of protein, Fig. 2⇑).
The release rate of silica can be used to estimate the lifetime of respirable talc particles in the body. The rate limiting step in the destruction of a mineral grain is determined by the rate of release of the slowest dissolving component (Hume and Rimstidt 1992). Estimates of particle lifetime were obtained by applying the measured silica dissolution rate to a geometric shrinking particle model. Particle geometry is relatively unimportant in the determination of the biodurability, since the variation in the geometry of shrinking particles (assuming dissolution from major surfaces) affects dissolution estimates by no more that about a factor of three. The major factor limiting the dissolution of magnesium silicates is the release rate of silica from the mineral surface, which may vary by several orders of magnitude.
For talc, the estimate of particle longevity was modeled using a “shrinking sphere” geometry. This approach was similar to that used by Hume and Rimstidt (1992) in their discussion of chrysotile dissolution. The shrinking sphere model assumes dissolution occurs evenly across the surface of the sphere. The time to dissolve the sphere is defined by the diameter of the particle, and is determined by the following relationship
where t is time (s), d is the particle diameter (m), Vm is the molar volume (m3/mol), and k is the rate constant (mol/m2 s). Application of the shrinking sphere model with the measured silica dissolution rate indicated an estimated lifetime of 8 years for a 1 mm talc particle.
The approach used to estimate the lifetime of talc in the body may be extended to other mineral dusts, provided that the rate constants for their dissolution are available. Established rate constants for selected silica phases and magnesium silicates are in Table 4⇓, which lists silica release rate constants at 37 °C (body temperature) and molar volumes for forsterite, chrysotile and quartz, for comparison with the our dissolution results. Hume and Rimstidt established the silica release rate from chrysotile asbestos at 37 °C over a pH range of 2 to 6. Incongruent dissolution of chrysotile was noted, with magnesium release to solution in excess of its stochiometric amount in chrysotile. A general rate law for silica release from forsterite was developed by Rosso and Rimstidt (2000). The release of silica from olivine is dependent on both pH and temperature and is 7.6 × 10−11 mol Si/m2 s at 37 °C and pH 7. The rate of silica release from quartz at 37 °C is 1.4 × 10−13 mol Si/m2 s (Rimstidt and Barnes 1980). The data in Table 4⇓ were used with the shrinking sphere model to calculate the curves relating particle size to estimated particle lifetime (Fig. 3⇓). The results indicate the wide range of biodurability associated with respirable sized mineral particles. Estimated particle lifetimes do not correlate with the Si:OH ratio of the minerals investigated. Similarly, calculated particle lifetimes based on silica release rates do not correlate with the polymerization of the silicate framework. For example, the estimated lifetime for a 1 μm diameter olivine sphere is greater than at that of a 1 μm diameter chrysotile sphere by a factor of approximately 6. Most of the difference in estimated lifetime results from the slower release of silica from the mineral surface.
A comparison of the rate of dissolution of talc with the rates of dissolution of other magnesium silicates shows an interesting trend. Because it is relatively easy to break Mg-O bonds compared to breaking Si-O bonds, it seems reasonable that the rate of dissolution of these minerals should be directly related to their Mg/Si ratio. Forsterite, with the highest Mg/Si ratio of 2/1, should dissolve at the fastest rate and the rate should slow with decreasing amounts of Mg until a pure silica phase (quartz or amorphous silica) with a ratio of 0/1 dissolves at the slowest rate. Although this analysis is consistent with the very fast dissolution rate of forsterite compared to amorphous silica, Table 4⇑ shows that it fails to explain the relative rates of talc and chrysotile.
One possible reason that for this difference is that three distinct but related dissolution processes exist for this series of minerals. The best documented is the hydrolysis reaction of Si-O-Si bonds by the nucleophilic attack by the negative end of the water dipole on Si as described by Lasaga and Gibbs (1990). The rate of this reaction is independent of pH and the reaction breaks bridging oxygen bonds to produce two Si-OH species. It is the only reaction responsible for the dissolution of pure silica. The other reaction is the electrophilic attack of a hydronium ion on the Si-O-Mg connecting oxygen, coordinated with the nucleophilic attack of water on the Mg, to produce Si-OH and hydrated Mg2+ species as described by Rosso and Rimstidt (2000). The rate of this reaction increases with decreasing pH because a hydronium ion participates in the activated complex. Because the forsterite structure consists of only Si-O-Mg bonds, this reaction is the only one responsible for its dissolution. The third process occurs because the remaining magnesium silicates consist of mixtures of Si-O-Si and Si-O-Mg and because the Si-O-Mg hydrolysis reaction proceeds much faster than the Si-O-Si hydrolysis reaction. The surfaces of these minerals quickly become depleted of Mg leaving behind a leached layer consisting of silica that has inherited a bonding topology from the dissolving mineral. The bonding in the leached layers is eventually modified by the formation of cross links as 2 Si-OH species react to form Si-O-Si and H2O as described by Casey et al. (1993). This cross linking process decreases the overall dissolution rate of these silica-enriched leached layers but they always dissolve at rates the are much faster than amorphous silica because the layers are always less polymerized than amorphous silica and therefore they dissolve at a rate that is significantly faster than amorphous silica. These faster rates are the result of the release of polymeric “chunks” of the leached layers rather than simple monomers (Weissbart and Rimstidt 2000; Dietzel 2000). These polymers subsequently dissolve in the solution remote from the mineral surface so the surface-normalized rate of dissolution appears to be very high. The rate of detachment of both silica monomers and polymers from the leached layer involves only the hydrolysis of Si-O-Si bonds and therefore the rate is independent of pH (Fig. 2⇑).
A comparison of the rates of dissolution of talc (this study) with the rate of dissolution of chrysotile (Hume and Rimstidt 1992) shows that the rate is more strongly influenced by the structure of the mineral than by the bulk chemistry. The dissolution rate of talc (Mg/Si = 3/4) is relatively slow because leached layers form only at the edges of the grains so the silica is released from a small part of the mineral surface. On the other hand, the dissolution rate of fibrous chrysotile (Mg/Si = 3/2) is relatively fast because the leached layer consists of a coiled sheet of silica that can unwrap from the lateral surfaces of the fibers. Perhaps this can be best visualized by comparing the difficulty of removing scraps of paper from the edges of a ream of copy paper vs. removing them from the free end of a roll of paper towels. Thus, understanding the rates of reaction between minerals and solution depends upon creating a model that is consistent with both the chemistry of the reaction and with the geometry of the reacting surface. Although the dissolution rates of the magnesium silicates do not correlate in a simple way to the mineral composition, they are easily explained in terms of a combined chemical and geometrical model.
Strict application of the geometric shrinking particle model may overestimate the lifetime of the talc particles. The geometric models assume that dissolution occurs evenly across the major surfaces of the geometric solid, and that one major dimension governs the particle lifetime. Talc likely does not dissolve evenly across its basal surface. Turpault and Trotignon (1994) noted that dissolution of biotite occurred primarily along the lateral surface of the crystals. If dissolution is restricted to the edges of the talc grains as opposed to the total measured surface area, the calculated silica release rate would increase in proportion to the decrease in surface area since the surface area is a factor in the denominator of the rate calculation. For instance, a 10-fold reduction in the modeled active dissolution surface would result in a corresponding 10-fold increase in the calculated silica release rate. An increase in the calculated silica release rate would result in decreased estimates of particle longevity in the body from application of the shrinking particle model, since this would indicate that the grains are dissolving more rapidly. Because our surface area measurements are of the total surface area of the talc sample, the lifetime estimate presented here should be considered a maximum estimate of particle longevity.
These results suggest there is no direct correlation between the dissolution rate of a particle under physiological conditions, and its potential to cause disease. Chrysotile dissolves quickly under physiological conditions, yet is considered a known human carcinogen and has been linked with development of fibrotic lung disease in elevated exposure conditions. Crystalline quartz dissolves very slowly in the body, and is associated with progressive lung disease related to both acute and chronic exposure to high silica dust concentrations. Making a clear correlation between crystalline silica exposure and development of respiratory cancer is problematic. Magnesium silicates with intermediate biodurability appear relatively innocuous.
The lack of direct correspondence between particle dissolution rates under physiological conditions and disease causing potential indicates that additional factors must be considered when evaluating the potential of a mineral dust to cause disease upon exposure. Particle morphology has been implicated in the carcinogenic potential of mineral dusts. Stanton et al. (1981) proposed that the shape of a fiber is the main factor in determining its carcinogenicity, however the implantation methods utilized by Stanton and co-workers may have increased the incidence likelihood of tumor production limiting interpretation of the data (Nolan and Langer 1992). The generation of free radicals, which has been tied to interactions between mineral surfaces and the physiological environment, has been linked to the disease process (Mossman 1992; Driscoll 1993; Werner et al. 1995). The surface properties of the minerals, and the effects of interactions between these surfaces and the physiological environment, likely play an important role in the disease process. Indirectly, particulate matter lodged in the respiratory system may affect the disease process, since the body deploys several defense mechanisms in response to the deposition of particles in the pulmonary system. These include mobilization of alveolar macrophages and other scavenger cells, which respond to the presence of foreign material in the body. The presence of foreign particles can result in the production of chemoattractant factors which serve to mobilize the body’s immune response (Driscoll 1993; Lehnert 1992). Several of the compounds released from activation of the macrophages have been linked to the development of fibrosis in the lung (see Driscoll 1993 and Lehnert 1992 for discussion of the pulmonary system response to inhaled particles). The presence of particulate matter in the airway, serving as a local stimulant to the inflammatory response, can cause damage to the cells of the pulmonary system. In this manner, the continued presence of the particulate matter should affect the disease development process.
The mixed flow reactor method described here is straightforward to implement and interpret and provides an effective way to simulate the dissolution behavior of minerals in the pulmonary environment. The dissolution rate of talc is 1.4 (±1.0) × 10−11 mol Si /m2 s and the rate is independent of pH and solvent chemistry, including the presence of organic chelators and proteins at physiological concentrations. This dissolution rate can be used with a shrinking sphere model to estimate a lifetime of 8 years for a 1 μm talc particle. The dissolution rates of silicates depend largely on the rate of silica release from the surface of the mineral grains. The relative biodurability of selected silicates is quartz>>talc>olivine>chrysotile. Mineral biodurability does not seem to be a strong factor in the development of pulmonary disease, since biodurability does not appear to correlate with the disease causing potential of mineral dust exposures.
ICP support was provided through the industrial hygiene laboratory of American Medical Laboratories (AML), Inc., of Chantilly, Virginia, and through HP Environmental Laboratories, Inc. of Herndon, Virginia. The assistance of Bryan Mason (AML) and Hugh Granger and SunBum Cambron (HP) with ICP analysis is greatly appreciated.
Manuscript handled by Jillian Banfield
- Manuscript Received February 10, 1999.
- Manuscript Accepted December 25, 2000.