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Bice Fubini
Università di Torino, Facoltà di Farmacia, Dipartimento di Chimica Inorganica, Chimica Fisica e Chimica dei Materiali, Torino, Italy
Key words : fibers, particles, asbestos, silica, hard metals, free radicals, iron, chelators, mixed dusts, glass fibers
This paper is based on a presentation at The Sixth International Meeting on the Toxicology of Natural and Man-Made Fibrous and Non-Fibrous Particles held 15-18 September 1996 in Lake Placid, New York. Manuscript received at EHP 26 March 1997; accepted 7 April 1997.This research was supported by Commission of the European Communities (Directorate General XII, Research and Technological Environment Department) project PL931359, and the Joint European Medical Research Board. The experimental work described was conducted in part by L. Mollo and G. Zanetti.
Address correspondence to Dr. B. Fubini, Università di Torino, Facoltà di Farmacia, Dipartimento di Chimica Inorganica, Chimica Fisica e Chimica dei Materiali, Via Pietro Giuria 7, 10125 Torino, Italy. Telephone: 39 11 6707566. Fax: 39 11 6707855. E-mail: fubini@silver.ch.unito.it
Abbreviations used: AM, alveolar macrophage(s); BET, Brunauer Emmet Teller method for surface area evaluation; Co, cobalt; MMVF, man-made vitreous fiber(s); PAHs, polyaromatic hydrocarbons; ROS, reactive oxygen species; WC, tungsten carbide.
In the early stages of pathogenic response, the function of the surface is mostly related to adsorption phenomena and cell-particle interactions. Adsorption may be either a primary step in toxicity or may inhibit adverse responses by blocking direct interactions between the particle surface and cell membrane.
Adsorption of xenobiotics prior to inhalation may transform the particle into a carrier of carcinogens in the lung, which may act synergistically with the particle itself ( 11 ). Polyaromatic hydrocarbons (PAHs) are adsorbed at the asbestos surface to a larger extent than on other solids such as silica or glass fibers ( 12-14 ). The surface concentration of PAHs attained is higher because on asbestos the PAH molecule is polarized and adsorbed vertically and not horizontally, as on silica. Multiple layers of vertically packed molecules build up and bind strongly to the surface ( 14 ). This may be related to the well-established synergistic effect of tobacco smoking and asbestos exposure on the risk of lung cancer; the relevant mechanism in still under debate ( 15 ).
Adsorption of endogenous material takes place in any body fluid and depends on the chemical characteristics of the surface such as charges, polarity, acidic-basic sites, and hydrogen-bonding potential ( 16 ).
By the time an inhaled fiber reaches the alveolar region, contact with body fluids has modified the external surface via physical adsorption of macromolecules. Surfactant treatments have been designed to model surface conditioning representative of initial events that occur when a particle deposits in the pulmonary alveolar space ( 17 ).
Interaction with cells may occur either with target cells that are directly damaged by the particle or with immune system cells attempting a defense against the foreign body, typically alveolar macrophage(s) (AM) and polymorphonuclear leukocytes. In the first case it is often hypothesized that DNA damage is caused by free radicals generated at the particle surface ( 11 ). The interaction with AM involves phagocytosis of the particle. In the lysosome the particle will experience a lower pH and a high concentration of oxidants, which may yield redox/radical reactions with consequent free radical release or chemical modifications at the surface of the particle itself.
Four major points must be stressed regarding any kind of particle:
Figure 1 . Membranolysis (hemolysis, %, empty symbol) and adsorption of water vapor (number of moles adsorbed under H 2 O vapor pressure of 5 torr, full symbol) on cristobalite mineral dust preheated at different temperatures. Data replotted from Hemenway et al. (34).
Any correct comparison between biologic responses to samples of the same material requires samples with the same chemical and mechanical and thermal history.
With equant particles, the biological response is often related to the extent of exposed surface ( 37 ). Some particles are smooth at the atomic level so that their geometric surface may be calculated from the size distribution and approaches the true one. With indented particles evaluation of the true exposed surface may be performed only by means of physical adsorption of gases (Brunauer Emmet Teller [BET] method). When comparing the effects of various particles, the question of measurement arises. How should exposure in vivo or doses in vitro be expressed: by mass (current method), number of particles, number of sized particles, or unit surface area? The choice depends on the biological process investigated. If small molecules act as mediators of biochemical reactions, the true surface area is the most appropriate one. If cellular events such as the internalization of particles are involved, the number of sized particles should be considered. However, the mass is the most inappropriate measurement to use, particularly if comparing effects of materials with different specific weights or different surface per unit mass. Table 3 suggests the most appropriate parameters to adopt for dose evaluation by following the biological response investigated.
In fibers, expression is more complicated, as length, diameter, and aspect ratio also must be considered ( 11 ).
The fibrous habit has always been considered a physical property of the material unrelated to chemical ones. Recently, however, some authors have reported different surface reactivity among fibers of the same composition but different sizes ( 17,38,39 ), which would suggest a possible chemical fiber effect, based mainly on different surface composition and/or adsorptive capacity of long versus short fibers.
Surface Hydrophobicity and Hydrophilicity
The degree of hydrophobicity of the surface regulates cell surface adhesion, protein denaturation at the interface, and selective adsorption of components from the liquid phase (
16
). A variation in hydrophilicity of the surface may involve a different translocation route in various biological compartments (Table 2), different coatings by endogenous materials, or different locations in close proximity to cells (
16
).
Heat treatment on crystalline silicas (cristobalite and quartz), which reduces the extent of hydrophilic sites (Figure 1), results in increased initial dust accumulation, increased recruitment of alveolar inflammatory cells, reduced short-term clearance, and enhanced long-term clearance. Heated quartz demonstrated a dramatic increase in particle retention in the lungs and in the rate of silica accumulation in the thymus and associated mediastinal lymph nodes, suggesting a relationship between the extent of hydrophobicity caused by thermal treatment and retention/transport in various biologic compartments ( 40 ).
Cristobalite fully hydrophobized by thermal treatment was inert both in vitro and in vivo ( 22,23 ). Chemically hydrophobized silica surfaces are also less pathogenic ( 41 ). This suggests that the pathogenic process is modulated by the extent of surface hydrophobicity, even if other surface functionalities are directly responsible for fibrogenic response to crystalline silicas ( 42 ).
Transition Metals and Free Radical Release
A large set of data from
in vivo
and
in vitro
tests indicates that antioxidants, ROS scavengers, and strong iron chelators ameliorate or inhibit the biological response to asbestos, which supports the hypothesis that iron-derived ROS would mediate genetic damage and play some role in asbestos toxicity (
11,43-45
). This hypothesis, still controversial, leaves unexplained the pathogenicity of iron-free fibers such as tremolite or ceramic fibers. However, it must be pointed out that a few traces of iron are sufficient to catalyze free radical generation; some iron may be deposited
in vivo
and originate catalytically active sites. ROS may be of endogenous origin, i.e., released following internalization or exogenous origin--the fiber itself generates ROS in biological fluids. There is evidence for both mechanisms occurring with some fibers, which implies radical release at the fiber surface ubiquitously, or, conversely, complex radical reactions during internalization between radicals of inorganic and biochemical origin (
43
). In both cases, the radical concentration attained may impair body defenses, and consequently, radicals may reach target cells.
The mechanism whereby a fiber promotes or catalyzes the abnormal release of radicals is still under debate. A crucial role in this reaction is played by the location of iron at the asbestos surface ( 43-45 ). Glass-, slag-, and rockwools also release free radicals in aqueous suspensions provided that iron is present in the fiber composition. ( 46-48 ).
The transforming potency on Syrian hamster embryo cells of various iron-containing solids was decreased by adding desferrioxamine, inferring that transforming potency is indeed related to iron ( 49 ). Not all iron was active, in agreement with a large number of cell-free tests indicating that only a small fraction of total iron present is capable of generating ROS ( 31,43,50 ).
Various hypotheses exist on the chemical nature of iron sites active at the surface and on their modifications in vivo following radical release ( 31,43-45,50-52 ). Reactive iron may be either at the solid surface linked in the crystalline matrix ( 31,38,50-52 ) or brought in solution by endogenous chelators ( 44,53 ). Single-strand DNA damage correlates with iron that may be mobilized from asbestos by low molecular weight chelators, which suggests a direct relationship between free radical generation and mobilized iron ( 44,53 ). However, a prolonged or catalytic mechanism is required to explain long-term pathogenicity, which may be sustained by an interplay between both surface and mobilized iron. Several recent papers indicate that iron complexed at the solid-liquid interface becomes very active ( 54-56 ). Adachi et al. ( 55 ) prepared a deironized crocidolite by washing the original fibers with HCl and EDTA, which was more potent in oxidizing DNA in vitro and in the induction of mesotheliomas in vivo . This is likely due to the fact that redox potential of iron, and related potential for free radical release, is modified and often enhanced following chelation. All of the above data are consistent with a model where the active iron is a well-dispersed ion, loosely fixed at the surface, and partly coordinated by various ligands.
The iron involved in the reaction-originating ROS may be in the chemical composition of the fiber (amphibole asbestos) or present as an impurity (chrysotile and glass fibers) ( 31,48-52 ). There is evidence that endogenous iron is deposited on the fiber surface from macrophages or other cells ( 57 ) that might also become active. This latter hypothesis might explain the toxicity of fibers that do not contain any iron e.g., ceramic fibers, but are carcinogenic in experimental animals.
Free radicals have been found in cell-free assays by different techniques, including direct spin trapping, oxygen consumption, lipid peroxidation, and DNA damage ( 43 ). Free radical release is not necessarily a catalytic reaction. The term "catalyzes" is often misused in place of the term "generates" in cases where no evidence was reported that free radical release was not just an outburst but a prolonged reaction. When the solid surface merely acts as a Fenton reagent:
particle+H
2
O
2
·
OH+OH
-
,
the reaction is indeed catalytic ( 52 ). Catalysis would then be confined to the phagolysosomal medium, where hydrogen peroxide is released following phagocytosis of the particle. In vivo , however, the situation may be different, as in some cases the surface active sites may be regenerated through redox cycles ( 43,50 ).
Inhibition of Silica Activity by Clays
The total amount of crystalline silica in coal mine dust does not correlate with pathogenicity. Several explanations have been proposed, including rank effect (relating toxicity to the geological strata of the coal deposit) and the role of clays in inhibiting the activity of quartz particles when in close contact with or actually covering the particle. Cytotoxity of these dusts relates better to free (uncovered) quartz than to total quartz content (
58
). Submicroscopic aluminosilicate coatings, recently evidenced on quartz, could also explain the rank effect in coal workers' pneumoconiosis (
59
).
Hard Metal Lung Disease: Activation of the Metal at the Carbide Surface
In recent years, clinical, epidemiological, and experimental evidence has accumulated indicating that Co metal particles, when inhaled in association with other agents such as metallic carbides (hard metals) or diamond dust, may produce an interstitial lung disease termed hard metal lung disease (
60-62
).
In vivo
and
in vitro
tests indicate that the pure components, namely Co metallic particles and pure WC, are inert. The pathogenic response is also different from that elicited by Co salts (
61,62
). Toxicity originates only when contact occurs with mixed dusts. Cell-free assays reveal that mixed dusts, not the pure components, release ROS in a buffered aqueous suspension, while Co is progressively solubilized (
63
). Co was not toxic per se, as Co soluble salts in contact with carbide particles are also inert. All data are consistent with the model illustrated in Figure 2, where atmospheric oxygen is activated at the WC surface by electron migration from Co to the carbide. In this case it is the mere contact between the particles, i.e., the solid-solid interface, which causes the reactivity related to the pathogenic response (
63
).
Figure 2 . Mechanism proposed for release of ROS from buffered aqueous suspensions of Co/WC mixtures (hard metals). Co is progressively oxidized and solubilized; oxygen is activated at the carbide surface (63). e - , electron.
Figure 3 . Adsorption of water vapor on vitreous fibers (MMVF10, MMVF11, MMVF21) and pure silica glass (Suprasil). Adsorption isotherms: adsorbed amounts as a function of equilibrium pressure.
We compared the adsorptive capacities of water vapor molecules of some artificial fibers with those of pure vitreous silica. Figure 3 illustrates the amount of water adsorbed as a function of the equilibrium vapor pressure (adsorption isotherms) for man-made vitreous fiber (MMVF)10, MMVF11, and MMVF21, and a ground pure silica glass (Suprasil). All glass fibers adsorb more water than pure vitreous silica under the same water vapor pressure because of coordination of water molecules with the exposed metal ions that are present in glass but not in silica. Their affinity for water, on a per-unit surface basis, is different, however, decreasing in the series
MMVF11>MMVF10> MMVF21>vitreous silica.
It is noteworthy that these fibers ranked in the same order when compared for biopersistence in vivo ( 64 ). If these findings could be validated on a much larger number of fibers, the number of water vapor molecules adsorbed by a given material might somehow predict, in a quick and simple way, the biopersistence of particles or fibers close in size and shape.
Iron chelators mobilize considerable amounts of iron from some asbestos, which modifies the surface and subsurface layers ( 44,50,53,65-67 ). Solubility in biological fluids containing molecules or anions that may chelate metal ions e.g., oxalate, phosphate, cysteine is much different from that in pure aqueous solution ( 66,67 ).
Scanning electron microscopy-energy dispersive spectroscopy investigations in our laboratory on ex- in vivo particles revealed that ion deposition is specific for each solid examined (unpublished results).
Major modifications take place in two cases: the formation of ferruginous bodies on asbestos (and few other kinds of fibers), and the progressive desegregation of chrysotile asbestos fibers.
Ferruginous bodies are the final product of a type of biomineralization that takes place on the surface of inhaled mineral fibers; endogenous iron deposits around the fiber, forming a thick, segmented coating of iron oxyhydroxides mixed with organic material ( 68-70 ). Long straight fibers are preferentially coated over short curled ones, but the percentage of coated fibers also depends on asbestos fiber type. In a recent Japanese study, a high number of asbestos bodies was found in a rather large cohort of patients. The number of coated fiber varied from 5% for chrysotile to 27% for amosite ( 71 ). This suggests that formation of asbestos bodies is related to both form and surface chemistry of the inhaled fiber. The biological significance of this process is still obscure ( 70 ). It is assumed to be a body defense mechanism attempting to isolate the fiber from direct contact with the lung. However, under some circumstances, the iron contained in the bodies may become redox active and trigger a series of deleterious reactions; amosite-cored asbestos bodies were responsible for the formation of single-strand breaks in DNA to a larger extent than uncoated fibers of similar size ( 72 ). If deposited iron is, or becomes, redox active, cycles of iron extraction and redeposition at the fiber surface may provide continous activation of the surface, releasing free radicals via the above mechanisms, which may account for long-term pathogenicity ( 43,50 ).
As opposed to amphiboles, which persist within the body virtually unchanged in their crystal structure, chrysotile is progressively split into fibrils and is eventually cleared from the lung, which makes the assessment of exposure to chrysotile sometimes difficult. This is due to its typical serpentine (layered silicate) structure, which is schematized in Figure 4. Chrysotile is a layered silicate; one [SiO 4 ] 4- layer alternates with a [Mg(OH) 2 ] (brucitic) one. Because the latter is larger, the sheets curl up, assuming the familiar fibrous characteristics. When leached with oxalic acid solutions, which mimics what may happen in vivo over long periods of time, the brucitic layers are solubilized, which leaves, in extreme conditions, just the silica framework. Leaching of chrysotile also occurs in cell cultures. It is more pronounced with AM than with pleural mesothelial cells, most likely because of differences in pH within the cells ( 73 ).
Figure 4 . The effect of leaching on chrysotile fibers: micromorphological modifications.
Surface area is increased by the leaching process, both because of the formation of empty cavities within the solid, and the splitting of bundles of fibers into fibrils (Figure 4). The adsorptive capacity of different kinds of small molecules e.g., water, ammonia, tert -butanol, even when measured per unit surface area, is much higher on leached than on unleached fibers. Figure 5 illustrates the adsorption of ammonia, measured on a per-unit surface basis, which indicates the presence of acidic surface sites. The above data indicate that in addition to the increase in specific surface, leaching imparts a different chemical reactivity to the surface. On leached fibers, strong adsorption of proteinaceous material may take place, which eventually would protect the body from direct contact with the fiber. However, adsorption of PAHs is weaker with leached than with the original chrysotile, which suggests that solids with a basic character (asbestos, magnesia) have more affinity for PAHs than those with an acidic one (silica, alumina) ( 14 ).
Figure 5 . The effect of leaching on chrysotile fibers: increase in adsorption capacity. Adsorption of ammonia (adsorption isotherms: adsorbed amounts as a function of equilibrium pressure) on original (empty symbol) and leached (full symbol) chrysotile.
As a consequence of surface differences, some biological responses to chrysotile fibers are also modified upon leaching: more cytoplasmic enzymes but fewer lysosomal enzymes were released with leached fibers than with unleached ones ( 74 ). The inactivation of human leukocyte elastase was greater on the leached fibers, probably in connection with their greater surface acidity ( 75 ), as was shown by its higher affinity for ammonia (Figure 5).
epidemiology
An understanding of the last point for toxic particles and fibers whose toxicity is well established could be of great help in designing safer new materials to be used as substitutes for pathogenic ones. The above sequence could be reversed in the following way:
mineralogy (identification of properties of pathogenic minerals)
Under these circumstances the knowledge of pathogenic minerals accumulated so far could be utilized to produce safer new materials and cell-free and in vitro tests could be used to prescreen new fibers and particles on the market and in the environment.
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Last Update: October 16, 1997