Document DM8Q9YEv3b5YDa4BqKZ45e1eB

FILE NAME Talc TALC DATE 1992 DOC TALC173 DOCUMENT DESCRIPTION Journal Article - Biological Effects of Inhaled Minerals 33 Guthrie GD 1992. American Mineralogist Mineralogist Mineralogist Vol 77 pp 225-243 American Mineralogist Volume 77 pages 225 2413992 Biological effects of inhaled minerals George D. Guthrie Jr. Geochemistry MS D469 Los Alamos National Laboratory Los Alamos New Mexico 87545 A ABSTRACT Numerous studies present data on the biological effects of inhaled minerals but these data are often disseminated within reports that primarily address the asbestos minerals Furthermore these reports are normally published in journals that are unfamiliar to most minerals scientists This review compiles these data in order to facilitate an understanding of the known biological effects of minerals An introduction to the types of studies from which the data were drawn is given so that those unfamiliar with such studies can assess the data critically In general minerals exhibit a range of biological activities from apparently inactive or slightly active such as hematite to highly fibrogenic and carcinogenic such as fibrous brucite nemalite The zeolites also exhibit such a range with some mordenite being slightly active and erionite being highly active however erionite is the only zeolite that has been studied extensively Although several mechanisms have been proposed to explain how minerals induce disease it is still unclear why minerals exhibit a range in biological activity The diversity of mineral species holds great potential for probing these mechanisms especially when mineralogical data are integrated with biological data Unfortunately many of the studies reporting data on the biological effects of inhaled minerals fail to report detailed mineralogical information hence it is difficult at present to interpret the biological activities of minerals in terms of their physical and chemical properties More collaboration between minerals scientists and health scientists would benefit this area of research by enabling an integration of mineralogical and biological data Important mineralogical data that are only rarely considered in biological research include exact mineral content of the specimen 1.e. identification and abundance of contaminants physical and chemical properties of minerals and surface properties of minerals INTRODUCTION Because of their potential to induce a number of lung diseases e.g. fibrosis lung cancer and mesothelioma the asbestos minerals fibrous serpentine chrysotile and fibrous amphiboles have been the focus of numerous experimental studies governmental regulations and extensive public concern Early studies of riebeckite miners Wagner et al 1960 revealed an association between exposure to riebeckite asbestos and mesothelioma a rare cancer with an extremely high morbidity rate Subsequently a higher than expected incidence of mesothehoma was found in American asbestos workers who were exposed primarily to chrysotile Selikoff et al 1964 1965 but also to amphiboles Ross 1984 which occurred more frequently in the lungs of these workers Langer and Nolan 1989 The widespread use of the asbestos minerals meant that a large population was exposed and potentially at risk and so began the proliferation of research on the biological effects of asbestos Fear of asbestos exposure led to a replacement of the asbestos minerals with substitutes and a skewing of the research on the biological effects of minerals toward the asbestos minerals Nevertheless a wide range of fibrous and nonfibrous minerals has been studied to some extent for potential health hazards although such data are frequently hidden within reports that focus on asbestos These data are important however for several reasons First all humans are exposed to mineral dusts from both anthropogenic and natural sources For example in a 45yr study on the mineral contents of lungs from residents of Tokyo Shishido et al 1989 found that by the early 1980s over 80 of Tokyo's residents had been exposed to mineral dusts Similar observations have been made in a variety of urban environments and nonoccupational exposure to mineral dusts can also result from living in a rural environment e.g. S^'bastienet al 1981 1984 Second various minerals are used both as replacements for asbestos and in numerous other commercial products and the health risks associated with these min- erals may differ from those associated with serpentine asbestos or with amphibole asbestos If minerals are to be used and regulated properly it is important to assess accurately the risk from exposure to each mineral and not simply assume that all fibrous minerals are equally hazardous 0003-004X 0304-0225 225 226 GUTHRIE EFFECTS OF INHALED MINERALS Third the mechanisms by which minerals in general including asbestos are toxic and carcinogenic can be more readily elucidated if differences in the toxicity and carcinogenicity of various minerals can be related to fundamental differences in crystal structure and crystal chemistry Collaborative efforts between minerals scien- tists and life scientists would be extremely effective at achieving this Unfortunately very few minerals scientists are involved directly in such research primarily because of scientific language barriers and a lack of familiarity with current issues in related mineral research In order to address the latter problem this paper will review the health risks associated with a variety of minerals Ross 1981 1984 reviewed the human health haz- ards associated with the asbestos minerals in a form ac- cessible to geoscientists and Mossman et al 1990 presented a review of the current issues in this research field These papers are useful starting points for anyone interested in the extensive literature available on asbes- tos Likewise the research on the the biological effects of silica is extensive and Heppleston 1984 provides an introduction to this literature However no such compilation exists for the literature on numerous other finegrained minerals The intentions of this paper are ) to compile the available data on the biological effects of clays exclusive of chrysotile zeolites and several other finegrained minerals 2 to facilitate a better understanding of the data by introducing the research techniques used in the studies from which the data were drawn and 3 to provide a foundation that can be used by minerals scientists interested in pursuing this area of research The intentions of this paper are to avoid any discussion of mineral regulation or the regulatory implications of the material reviewed Though many of the minerals covered in this review are toxic carcinogenic or both in some tests the risk to humans exposed under normal conditions may be minimal As will be noted many of the experiments used to assess the pathogenicity of a mineral investigate the mechanisms of pathogenicity or evaluate the pathogenicity of a specific mineral relative to other minerals These experiments do not necessarily emulate typical conditions of human exposure hence the results may not reflect the exact response that would be expected in humans The assessment of risk from exposure to a specific mineral is an extremely involved task The interested reader is directed to the article by Mossman et al 1990 for an introduction to the problem anda list of pertinent references Current federal regulations including those for minerals can be found in Codes of Federal Regulations CFR 29 part 1910.1000 CFR 29 is revised annually on July 1 and is found in most libraries INTRODUCTION TO BIOLOGICAL REPORTS Determination of a substance's biological activity Exposure to mineral dusts has been linked with a variety of lung diseases Exposure to a fibrogenic mineral can result in fibrosis production of scar tissue in the lung which can impair the function of the lung Exposure to a tumorigenic or carcinogenic mineral can result in cancer such as lung cancer or mesothelioma Lung cancer is associated with exposure to a variety of substances eg eg , cigarette smoke in addition to minerals but mesothelioma or cancer of the mesothelium lining of the abdominal wall is commonly associated exclusively with exposure to fibrous minerals predominantly the asbestos minerals The potential for a specific mineral to induce these diseases can be evaluated by numerous techniques each of which provides different information and has different factors that complicate interpretation As pointed out by Rall 1988 there are four basic groups of methods used to determine the carcinogenic potential of a substance epidemiological studies in vitro studies in vivo studies and prediction of biological activity by comparison with a similar m~-neralstructure relation- ship Epidemiological studies In an epidemiological study a substance's health risks are evaluated by determining the relationships between human exposure to a substance and the potential health effects One approach to epidemiological studies uses cohorts or groups of individuals whose lifestyles are similar to monitor the incidence of disease in response to exposure to a substance Ideally two groups are chosen such that their difference is only in the exposure to a specific substance thus one group serves as a control against the health effects from other agents In many studies however no explicit control group is used but the study group is compared with national averages Epidemiological data are commonly reported using a standardized mortality ratio SMR that com- pares the observed death rate from a disease in the study group with the rate expected based on the control group Another approach to epidemiological studies uses case studies to determine lifestyle patterns of individuals afflicted with a disease In both approaches it can be difficult to assess the effect of other harmful substances to which individuals were exposed such as other mineral dusts or tobacco In other words an epidemiological study looks for patterns in the incidence of a disease and thus permits only an indirect determination of the cause of that disease An obvious advantage of an epidemiological study however is that it attempts to determine the actual effect of mineral exposure on humans exposed under typical conditions An important aspect of epidemiological studies is the characterization of exposure which can be achieved by a number of techniques A dust's mineral content particle size and shape and areal distribution can be measured directly in an environment by collecting air samples or soil or dust samples Such measurements are useful for providing detailed information concerning current exposure conditions However onset of disease can occur 20-30 yr after exposure to a mineral dust and current exposure conditions may differ significantly from previous exposure conditions Furthermore dust characteris- GUTHRIE EFFECTS OF INHALED MINERALS 227 tics may fluctuate in some environments causing an in- correct estimation of exposure A direct characterization of the dusts to which an in- dividual was exposed can be made by analyzing lung tissue or expectorated sputum A variety of processes occur in the lung following exposure to dust Lehnert 1990 Schlesinger and Driscoll 1989 and many of these result in a clearance of dust particles via the mucociliary escalator within the lung and trachea Thus sputum provides a means of directly sampling some of the dust particles being cleared from the respiratory system This process can continue over a prolonged period after exposure Frequently these particles become coated with ferruginous material believed to be derived from proteins such coated particles are referred to as ferruginous bodies Particle concentration in the sputum has been used as an indication of current particle content in the lung S^'bastien et al 1984 Analysis of sputum samples is compara- tively simple and inexpensive However high lung burdens 10000 ferruginous bodies per gram of dry lung S^'bastienet al -are required before particles are detected and exposure estimates are biased to the extent that the sample includes only those particles being cleared An accurate assessment of the mineral content of lungs can be obtained even for lower lung burdens by analyzing lung tissue obtained during surgery or a postmortem examination e.g. Churg et al 1984 However biopsy of lung tissue is complicated by the heterogeneous variation of particle deposition and retention at different sites within the lung so lung samples are needed from several locations to estimate an average lung burden Incidence of disease is typically estimated by several methods Clinical examination of risk individuals combined with chest rays can often detect early indications of disease but to assess the subjective factors associated with the grading of a chest ray the same set of rays must be read by several individuals Death certificates provide another means of estimating the incidence of disease However this method can result in incorrect estimates since the accurate classification of a specific disease often requires more extensive analysis than is commonly performed during a postmortem exam~-nation Finally in some cases biopsies can be performed on lung tissue from diseased individuals and lungs and other organs can be removed and examined after an individual from an exposed group has died as is done with asbestos workers in South Africa for example Even so there is some concern that neoplasias malignant tumors can be classified incorrectly resulting in either an over- estimation or underestimation of the incidence of disease In vivo studies Animal models are used extensively to study the effects of exposure to mineral dusts Ideally an animal species is chosen such that its response to a specific substance closely resembles the response observed in humans under similar conditions With such an animal model the complete biological effect of a substance can be studied under various exposure conditions In prac- tice however responses observed in animal models are not identical to responses observed in humans so prediction of a human response using results from an in vivo experiment is not always straightforward In mineral research rats and mice are the most commonly used animal models however guinea pigs sheep dogs hamsters monkeys and rabbits have also been used Pott 1980 reviewed some of the in vivo experiments concerning the biological effects of mineral fibers and dis- cussed the differences in response among species Because disease must be induced more rapidly in an~-- mals than it is induced in humans in vivo experiments commonly use exposure methods that differ significantly from exposure conditions experienced by humans Disease in humans often occurs up to 20-30 yr after initial exposure to a dust however most lab animals live less than 20-30 yr Hence disease is induced more rapidly in an in vivo experiment than would be expected under natural exposure conditions Typical in vivo experiments employ one of three exposure methods 1 intratracheal injection of a saline solution into the target organ 2 direct application of the dust to the target organ e.g , intrapleural and intraperitoneal instillations or 3 inhalation in a dust environment e.g. 1-50 mg or ~ 500-2500 fibers The current regulatory standard for occupational asbestos exposure in the U.S. is 0.2 fibers however 50 of all asbestos exposure levels in U.S. schools lie within 10-6-10 fibers according to the Environmental Protection Agency 1986. The route of entry for the dusts in such experiments clearly differs substantially from the typical route of entry in humans inhalation in a comparatively poor environment However even for inhalation experiments conducted with reasonable dust levels exposure would differ from that expected in humans since the differences between the respiratory systems of laboratory animals and humans e.g. airway size and shape breathing patterns clearance mechanisms introduce a sampling bias on the particles reaching the lungs e.g. Oberd^rsterand Lehnert 1990 Short 2 y3r an~-malexperiments also inadequately model human exposure in that short experiments do not consider the term 10-30 yr alteration of mineral particles such as dissolution or surface modification by the biological medium In vivo studies can provide important information such as ( the effect of mineral dusts on a living organism including types incubation periods and severity of diseases translocation migration and clearance rates of particles from the site of initial exposure and cellular responses to exposure 2 the effect of various exposure conditions 3 an evaluation of the risk to humans 4 the elucidation of pathogenic disease causing mechanisms and 5 the identification of potential treatment methods However such experiments are time consuming up to several years duration expensive and difficult to interpret unless a very strong or very weak effect is found Rall 1988 Furthermore the use of data from in vivo experiments to predict human response can be complicated by a variety of experimental factors including 228 GUTHRIE EFFECTS OF INHALED MINERALS differences between human and animal response to ex- posure the degree and method of exposure and the use of animal strains particularly susceptible or resistant to disease These two last factors additionally make comparison of results from different studies difficult unless identical experimental procedures were used When provided in the original report animal strains will be included here in the review of in vivo data to allow com- parisons to be made between studies In vitro studies In vitro experiments use specific cells to determine a mineral's biological activity and are commonly used because they are rapid and relatively inexpensive One of the more commonly used in vitro methods is the Ames test Ames et al 1975 which uses mutation rates in bacteria as a measure of carcinogenic potential However the asbestos minerals are one of only two suspected carcinogens the other being conjugated estrogen that do not appear mutagenic in a bacterial assay Chamberlain and Tarmy 1977 Shelby 1988 The implications of this remain incompletely understood Eukaryotic mammalian cells are also used for in vitro experiments to test a mineral's biological activity with red blood cells RBCs macrophages and epithelial cells being the most commonly used cell types These cell types are also found in the lung where they can potentially interact with inhaled dusts Hemolysis experiments test the ability of a substance to destroy or lyse RBCs by incubating RBCs in contact with the substance and then measuring cell viability the release of hemoglobin is an index of cell destruction In vitro experiments with other cell lines also test for cytotoxicity the ability of a substance to kill a cell normally either by 1 the cellular exclusion of a vital dye where dead cells allow penetration of the dye but living cells do not 2 the reduction in the ability of the cells to develop into colonies or 3 the release of enzymes indicative of an increase in membrane per- meability or cell death where membranes of healthy cells are impermeable to the enzymes Heppleston 1984 pre- sented an excellent discussion of information that can be derived from cytotoxicity experiments In addition to their use in determining cytotoxicity in vitro experiments can be used to determine the genotoxicity ability to affect genetic material or mutagenicity ability to cause mutations of a substance As mentioned above the Ames test is one such technique Other methods involve a quantification of mutation by measuring processes involving chromosomes or DNA directly such as sister chromatid exchange SCE or unscheduled DNA synthesis O radicals such as the superoxide anion are believed by some investigators to participate in both fibrosis and carcinogenesis Mossman et al 1989 Mossman and Marsh 1989 and the measurement of the gen- eration of such anions by a catalytic reaction involving a mineral surface Pezerat et al 1989 is another potential indicator of a particle's mutagenic activity Structure relationship The simplest and least expensive method to determine the potential health hazards of a mineral dust may eventually prove to be the prediction of a mineral's biological activity by comparison with known structure relationships However an accurate knowledge of the mechanisms by which a mineral is toxic is essential for this method to be effec- tive Several mechanisms are currently proposed to explain the biological activities of minerals Table 1 and Fig ) However these mechanisms remain too poorly understood to allow an accurate prediction based on a mineral's structure Nevertheless such predictions are made primarily based upon the observed correlation between biological activity and particle shape and size e.g , Stanton et al 1981 It is interesting to note that many of the proposed mechanisms for induced disease involve chem- ical reactions e.g. reduction that are similar to reactions that occur in a geological environment A geochemist's approach to the study of such reactions differs greatly from the approach taken by most biological scientists Consequently geochemists can contribute enormously to the study of induced diseases One role for the geochemist is the identification and characterization of active sites on mineral surfaces the results of which would be of interest to both geologists and biologists By characterizing the appropriate physical and chemical aspects of each sample biological activity can be related to a measurable parameter e.g. surface area Lewis sites per surface area Br^,nstedsites per surface area and a model for biological activity can be developed Furthermore a sound mineralogical approach would facilitate the design of biological experiments that control most potentially active mineralogical characteristics while allowing the active site of interest to be studied For example numerous experiments have been conducted to test the biological activity of fibrous amphiboles As shown in Figure , however amphiboles have numerous potentially active sites Hence the results of a study on the toxicity of amphibole cannot be associated with one particular active site Conversely if experiments were conducted using two amphiboles that differed only in the composition of the octahedral site then the activity of polyvalent cations in amphiboles active site 3 on Fig ) could be determined The diversity of mineral species offers a unique potential for characterizing the activity of numerous mineralogical characteristics In addition to natural samples synthetic minerals could be used effectively e.g. by growing zeolites with identical framework topologies but with various amounts of tetrahedral Al Mineralogical aspects Mineral names In principle usage of nomenclature to describe a mineral should follow strict guidelines For species names these guidelines are widely accepted and have been developed so that a mineral name provides important information concerning both structure and composition For example the nomenclature for amphiboles is extremely complex and relies on a knowledge of the composition and structure of a given amphibole spec- GUTHRIE EFFECTS OF INHALED MINERALS 229 TABLE 1. Mechanisms of induced disease Proposed mineralogical mechanisms Proposed biological mechanisms Br^,nstedsites proton sites associated with underbonded O atoms resulting from either cation substitutions or broken bonds at a mineral surface Lewis sites acceptor sites associated with polyvalent cations cation sites easily exchangeable cations e.g , amphibole A site or ze- olite cage site Specific surface periodicities periodicities that promote a specific interaction with a particular molecule e.g. particle interactions reported by Appel et al 1988 Oxidative stress resulting from the catalytic production of oxygen radicals at a mineral surface Genetic alteration by a number of mechanisms including transfection of intercellular DNA and particle interaction during mitosis Incomplete phagocytosis resulting in the release of cytotoxic enzymes by the cell Note There is no implied correlation between opposing mineralogical and biological mechanisms imen Leake 1978 Hence use of the species name rie- beckite defines a mineral as a clinoamphibole i.e. a dou- chain silicate with a specific stacking order with a composition of Na F Varie etal names how- ever are not so strictly defined So although the varietal name crocidolite is commonly used to describe asbes- tiform riebeckite the identification can be based on the blue color and asbestiform habit but not on composition- al or structural information Numerous examples illustrate the problems that can result from inaccurate usage of mineral nomen- clature Amosite is a term used to describe brown as- bestos The term originates from an acronym for the Asbestos Miners of South Africa Although the term is frequently used to describe asbestiform cummingtonitegrunerite it has also been used to describe ores containing mixtures of asbestiform amphiboles This ambiguity has led to conflicting definitions of amosite i.e. amosite has been defined as a varietal name for asbestiform ferro- gedrite by some e.g. Roberts et al 1990 Hence the term amosite provides limited information pertaining to the mineral content of the sample In reports on the effects of zeolites erionite and mordenite are often referred to as fibrous and nonfibrous equivalents despite the fact that both are normally fibrous and have different structures and composition Furthermore the identification of one or the other is typically made using qualitative analytical TEM ATEM based on the presence or absence of specific exchangeable cations Similar examples of the incorrect usage of mineral names occur throughout the literature on the health effects of dusts Hence the reported mineral content is potentially suspect unless adequate data were used for identification The lack of interest in the importance of a mineral's structure and composition is further demonstrated by data Fig 1. Schematic diagram of the amphibole structure viewed along the c axis Numbers indicate possible active sites 1 site cations 2 protons associated with Al substitution in the tetrahedral sites 3 polyvalent cations in the octahedral sites 4 protons associated with underbonded O atoms sheets for the asbestos minerals Both the National Insti- tute for Occupational Safety and Health NIOSH and at least one major supplier of asbestos for biological research provide data sheets listing incorrect mineral for- mulae for the asbestos minerals Such incorrect information may form the basis of mineral identification or interpretation of results used in some studies on the health effects of asbestos Because ofthis casual usage of mineral nomenclature it is difficult to interpret the results ofa study in terms of mineralogical properties such as structure and composition The improper use of mineral names is comparable to an incorrect usage of nomenclature for cell type or animal species If a report stated that rodents were used in the experiments or worse rats were used in the experiments when in fact the experiments were conducted on mice the data would be extremely difficult to interpret Most reports on the in vivo effects of minerals are extremely specific in describing animal species and cell types yet they often fail to identify mineral species correctly Unfortunately the advantages of a strict usage of mineral nomenclature are not fully appreciated by many scientists involved in related mineral research including both minerals scientists and nonminerals scientists Sample purity Another source of uncertainty in these studies concerns purity of the mineral dust Detailed description of the mineral content is rarely given and identification of the minerals generally relies upon that made by the supplier Even when obtained from reliable sources however the exact mineral content of a dust is suspect Most suppliers provide mineral samples that contain mixtures of minerals even though one mineral may be 230 GUTHRIE EFFECTS OF INHALED MINERALS the dominant constituent Mineral impurities even in small quantities may have a significant effect on a biological response For example recent studies e.g. Churg et al 1984 show that the lungs of workers exposed to chrysotile contain abundant amounts of fibrous tremolite a minor contaminant of chrysotile ores Churg et al 1989 found that the rate of mesothelioma is strongly correlated with tremolite but much less so with chrysotile Continuing with the analogy above the use of impure mineral samples is equivalent to running an in vitro assay with lung cells which would consist of several types of cells e.g. macrophages and epithelial cells This would never be done in an in vitro experiment as each cell type responds differently Mineral identification Most of the studies reviewed below generally characterized samples by light microscopy or transmission electron microscopy TEM and less commonly by ATEM Electron diffraction analysis is rarely used to determine mineral content despite the fact that most of the particles cannot be identified uniquely based on morphological and compositional data alone Particle identification by TEM can be time consuming when large numbers of particles are included especially when ATEM and electron diffraction are used Hence results are potentially affected by poor counting statistics and incorrect identification of the particles when electron diffraction is not used Minerals present in dust can also be determined by quantitative ray diffraction XRD Davis 1990 measured reference intensity ratios RIRs for chrysotile and amphibole asbestoses and demonstrat- ed that the minerals in asbestos mixtures can be deter- mined with a lower detection limit of 0.5-2.0 wt Puledda and Marconi 1990 also reported a low detection limit 2 ...gfor chrysotile in various matrices Chipera and Bish 1989 and Bish and Chipera 1991 used RIRS to determine erionite concentrations in dusts and reported detection limits as low as 100 ppm Quantitative analysis of mineral content using the Rietveld method with ray diffraction data Snyder and Bish 1989 may prove to be even more successful than the use of RIRS since the Rietveld method effectively addresses problems associated with peak overlap and compensates somewhat for the high degree of preferred orientation exhibited by fibrous and platy minerals However no biological studies using this approach have been reported to date Assessing human risk As indicated above many of the results of experiments on induced pathogenesis do not relate directly to risks to humans For example though a mineral may be highly active in an in vitro assay it may pose little risk to humans under normal conditions e.g. kaolinite Human response relates to a number of factors including the pathogenicity of the sample residence time in vivo dose and variations in individual response e.g. physical condition of the person smoking history propensity toward a specific disease Hence a mineral such as kaolinite may be highly active at the cellular level but it does not reside long enough in the lungs to induce disease Alternatively a mineral may show a positive response in a given assay but the mechanism tested by the assay is not involved in pathogenesis in humans REVIEW OF DATA Numerous data are reported that describe the biologi- cal effects of mineral dusts However most such studies provide only limited mineralogical detail Hence the re- sults from these studies may not reflect results one would anticipate from a mineralogically pure sample Studies that reported only limited mineralogical data may have used samples that were 1 mineralogically homogeneous containing the mineral described 2 mineralogically het- erogeneous containing numerous minerals or 3 mineralogically homogeneous containing a mineral different from the one described In general it is not possible based on the published data to determine to which category a sample belongs In the absence of data to the contrary I believe it should be assumed that the mineral content of a sample is as described by the original investigators Nevertheless this adds uncertainty to any interpretation based on these data and this uncertainty should be rec- ognized In order to clarify these uncertainties some investigators have supplied me with their samples and these samples are being characterized using quantitative ray diffraction analysis Guthrie and Bish unpublished data Where preliminary results are available these will be given Those investigators that have supplied samples are commended for their desire to augment their studies with detailed mineralogical information For those studies that did present mineralogical infor- mation ranging from a generalized locality to complete descriptions including compositional analysis the mineralogical detail will be included with the summary of results When no mineralogical information was given only a mineral or material name will be listed Related to the poor mineralogical detail is potentially inaccurate usage of mineral names The use of unaccepted mineral names rock names and compound names is rampant in the biological literature Some as- sumptions therefore were made in order to categorize these studies with respect to mineralogy For instance for the purpose of categorizing it was assumed that Fe O and iron dust refer to hematite bentonite refers to montmorillonite and attapulgite refers to palygorskite the quoted terms are retained in the review to allow the reader to recognize assumptions by the author Furthermore when mineral group terms such as carbonate or mica were used these are also retained in the review This is not meant to imply that either the quoted terms or the mineral group names are mineral names but rather it serves to categorize the study as appropriately as possible based on the probable major mineral Oxides and hydroxides Most studies on oxide- and hydroxide dusts suggest that some samples can produce fibrosis in vivo GUTHRIE EFFECTS OF INHALED MINERALS 231 but are generally relatively inactive minerals Exceptions may include oxides containing Cr not necessarily mineral samples and fibrous brucite Fibrous brucite may in fact be extremely active with exposure resulting in fibrosis carcinogenesis or both Hematite Epidemiological studies suggest that exposure to hematite dust alone under modern mining conditions low dust exposure ventilation wet drilling not increase the risk of lung cancer However individuals exposed under unfavorable mining conditions high exposures to dusts especially when contaminated with silica radon and tobacco smokedo show a higher than expected incidence of respiratory disease Lawler et al 1985 found no overall excess of mortality due to lung cancer SMR = 0.97 for all cancers and SMR -- 0.94 for lung cancer SMRs based on U.S. white males among 10403 underground miners in Minnesota who were exposed to iron dust hematite + limonite silica phosphates and other oxides as given by Lawler et al 1985 In fact they found a lower than expected mortality for respiratory disease overall SMR ===== 0.79 However they reported no information about exposure conditions i.e. quantitative mineral content of the dusts particle sizes or mass concentrations Lawler et al agreed with suggestions by previous workers e.g. Boyd et al 1970 Radford and Renard 1984 that observed excesses in mortality due to lung cancer in ironore miners reflect exposures to other factors such as radon and radon daughter products RRDs silica tobacco smoke and diesel fuel since exposure to these factors was minimal in their cohort compared with cohorts of iron- ore miners studied previously Chen et al 1990 also suggested that exposure to RRDs and silica could explain excesses of mortality due to lung cancer in hematite miners They studied 6444 male workers associated with hematite mining in China 5406 of whom were involved in underground operations and reported SMRs based on specific death rates for Chinese males for lung cancer ranging from ~ 1.0 at the 95 confidence level for medium dust exposure to 27 for heavy dust exposures However exposure to RRDs is highly correlated with dust exposure hence the individual effects of the two could not be separated Incidences of other respiratory diseases such as silicosis and tuberculosis are also correlated with the incidence of lung cancer but no data on silica exposure were given Cigarette smoking shows a positive relationship with lung cancer as well as indicated by an SMR for lung cancer in smokers of 2.7-6.3 95 confidence interval or CI In the cohort of Chen et al the use of modern mining conditions wet drilling and ventilation has lowered airborne dust exposure significantly from > 100 mg to < mg mand workers exposed only under the improved conditions may show a lower SMR for lung cancer 1.1-4.6 95 CI than those first exposed prior to the use of wet drilling and ventilation 2.9 7.9 4 5 CI In vivo experiments indicate that hematite samples are biologically inactive Pott and coworkers Pott and Friedrichs 1972 Pott et al 1974 found no fibrosis or tumors in 80 Wistar rats 530 d after intraperitoneal injections of hematite source not given whereas in the same study Wistar rats showed fibrosis and up to a 40 incidence of tumors when injected with chrysotile and a 55 incidence of tumors following the injection of silica glass Vorwald and Karr 1938 found that hematite dust induces no tumors in guinea pigs or rats following inhalation of the dust no information was given concerning the source of dusts or exposure levels However asbestos type not given also failed to induce tumors in guinea pigs in the same experiment Finally Mossman and Craighead 1982 found that hematite IIT Research In- stitute Chicago does not induce tumors in golden Syrian hamsters following subcutaneal implantation of in vitroexposed tracheas however hematite is nearly as effective a cocarcinogen as riebeckite asbestos Union Internatio- nale Contre le Cancer UICC standard when pretreated with a polycyclic aromatic hydrocarbon In vitro experiments suggest that hematite samples are noncytotoxic and nongenotoxic Dubes and Mack 1988 used an in vitro technique to test the ability of a variety of materials to mediate the transfection of mammalian cell cultures transfection of cells is the pro- cess of introducing foreign genetic material into a cell and is one proposed mechanism for the carcinogenicity of mineral dusts e.g. Appel et al 1988 Their data show that Fe2O3 reagent grade from Matheson Coleman and Bell Company is only slightly effective as a mediator For comparison asbestos from a variety of sources and Cr fOrom Matheson Coleman and Bell were 3-7 times more effective mediators Witmer and Cooper 1983 also reported that Fe2O3 is nonmutagenic whereas Cr iOs mutagenic as determined in a modified Ames test Boehmite goethite and lepidocrocite In vivo experiments suggest that samples containing iron and aluminum hydroxides may be slightly active in the lung Inhalation experiments by Gardner et al 1944 showed no effect of boehmite laths measuring 75 ^ 300 nm mineral identification confirmed by King et al 1955 using TEM and XRD on the lungs of guinea pigs However using the same material King et al 1955 observed that severe and rapid pulmonary fibrosis develops in rats after a direct injection of boehmite solution into the lungs Stacy et al 1959 extended the study by King et al 1955 to include an additional sample of boehmite better crystallized and having a mean size of ~ ...m and samples of goethite and lepidocracite presumably lepidocrocite measuring 0.5 ...mand -0.5 ^ 2 ...m respectively They demonstrated that the boehmite sample used in the experiments by Gardner et al 1944 produces a dependent fibrogenic response whereas the grained crystallized boehmite is much less fibrogenic Goethite- and lepidocrocite samples however are only slightly fibrogenic even at higher doses than boehmite Inhalation experiments by Campbell 232 GUTHRIE EFFECTS OF INHALED MINERALS 1940 using the precipitated brown oxide of iron Fe2O3 H BOritish Drug Houses produced a 22.7 incidence of lung tumors in mice compared with 6.8 in the con- trol group and 17.6 in a group exposed to precipitated silica dust tumors did not develop until after 300 d with most developing 600 d 900after first exposure An- imals were exposed to 0.5 g of dust per hour 6 h per day 5 d per week for 1 yr Brucite In vivo experiments suggest that samples con- taining fibrous brucite described as nemalite in most studies are both fibrogenic and carcinogenic Pott and coworkers Pott and Friedrichs 1972 Pott et al 1974 found that fibrous brucite when intrapleurally injected in Wistar rats produces fibrosis comparable to that produced by silica or chrysotile injections and exhibits a tumor rate 62.5 exceeding those of silica 55 and chrysotile 40 palygorskite however exhibits a 65 tumor rate in the same test Wagner et al 1973 found that 20 mg of a sample containing fibrous brucite administered to Fischer 344 rats by intrapleural injection induces mesotheliomas at a rate of 56 Their sample was obtained from a Canadian mine and contained chrysotile though no estimate for the amount of chrysotile contamination was given It should also be noted that chrysotile from this same mine induces mesotheliomas under the same conditions at a slightly higher rate 61 In vitro experiments further indicate that samples con- taining fibrous brucite are cytotoxic to a variety of cell lines Chamberlain and Brown 1978 showed that fibrous brucite same material as used by Wagner et al 1973 reduces the forming efficiency of Chinesehamster lung cells at doses roughly equivalent to those for a comparable cytotoxic response in experiments with either amphibole or serpentine asbestos The dose required to reduce cloning efficiency to 50 is 12 mL for fibrous brucite compared with 9 mL for riebeckite asbestos and 17-26 mL for chrysotile talc is nontoxic at 50 mL the highest dose used Jaurand et al 1980 found that fibrous brucite is cytotoxic to human RBCs and rabbit alveolar macrophages They demonstrated that both the hemolytic and cytotoxic activities of fibrous brucite are intermediate to those of chrysotile or riebeckite asbestos Finally Pezerat et al 1989 found that fibrous brucite is comparable to chrysotile and much more effective than amphibole asbestos in its ability to catalyze the production of O radicals a step of potential importance in both fibrogenesis and carcinogenesis The 1 layer silicates and chlorite Most studies of samples containing 1 layer silicates or chlorite suggest that some samples can produce fibrosis or tumors in vivo and can be highly active in vitro However epidemiological data on exposure to kaolinite ing dusts suggest that fibrosis is induced only in extraordinary conditions i.e. high exposures or in the presence of other pulmonary complications Although these minerals may be cleared rapidly from the lung and hence are not pathogenic in humans their in vivo and in vitro activities may provide clues to the mechanisms of min- induced pathogenesis Kaolinite and halloysite Epidemiological studies suggest that kaolinite dust is fibrogenic only under extraordinary conditions i.e. high dust conditions or exposure combined with another respiratory disease such as tuberculosis Hale et al 1956 reported case studies of seven kaolinite workers primarily baggers exposed to extremely high dust conditions who showed indications of respiratory disease as determined by clinical examinations including chest rays Autopsies of two of the men revealed fibrosis associated with large amounts of kaolinite mica and amorphous silica One of the autopsies however also noted tuberculosis dead tuberculosis bacilli enhance the fibrogenic effect of kaolin dust in animals Kettle 1934 Attygalle et al 1954 Similar observations were reported in a case study by Lynch and McIver 1954 In a cohort study Sheers 1964 found fibrosis in up to 13 of kaolinite workers exposed to high dust levels Tuberculosis was uncommon in his cohort However fibrosis was highly correlated with high dust exposures and length of employment More recent studies confirm that exposure to high dust levels particularly bearing dusts during kaolin mining can be correlated with abnormalities in chest rays e.g. Kennedy et al 1983 Oldham 1983 Sepulveda et al 1983 Ogle et al 1989 However some of these abnormalities may not reflect the onset of fibrosis Oldham 1983 Lapenas et al 1984 confirmed the presence of kaolinite in pul- monary tissue from five kaolin workers with pneumoconiosis silica was not present in the lung samples In vivo experiments reported thus far on the fibrogenic potential of kaolinite dusts are inconclusive Kettle 1934 observed no fibrosis in guinea pigs following intratracheal injection of kaolinite British Drug Houses the sample contained quartz and very numerous sericite fibers though as indicated above he did find that exposure to kaolinite and dead tuberculosis bacilli does result in fibrosis King and Harrison 1948 used direct injection into the lung to study the effects of two kaolinite samples on rats Unfortunately one of the experiments used kaolinite samples containing 35.68 wt carbonate minerals species not given whereas in the other experiment which used a comparatively pure sample of kaolinite only two rats survived more than 10 d after exposure Neither of these rats developed fibrosis Mossman and Craighead 1982 found that kaolinite 3-5 ...min diameter Georgia Kaolin Company does not induce tumors in golden Syrian hamsters following subcutaneal implantation of in exposed tracheas and is a slightly less effective cocarcinogen than UICC crocidolite when pretreated with a polycyclic aromatic hydrocarbon Inhalation experiments by Wagner 1990 produced no lung tumors in 20 rats probably from the Wistar strain exposed over a period of 3-24 months but a slight fibrogenic response was observed His samples contained 8595 kaolinite with the remainder consisting of mica feldspar and quartz For comparison a nonfibrous ze- GUTHRIE EFFECTS OF INHALED MINERALS 233 olite and a long attapulgite produced more severe fibrogenic responses Wastiaux and Daniel 1990 also used inhalation methods to assess the fibrogenicity of kaolin They reported that their kaolin sample Cornish kaolin dust induces a moderate fibrogenic response in Wistar rats Long experiments currently in progress by Maltoni and coworkers Maltoni et al 1982 Maltoni and Minard~- 1989 may provide additional information on the in vivo activity of kaolinite In vivo studies using halloysite samples however suggest that this kaolin mineral may be carcinogenic Stanton et al 1981 found that two samples of halloysite obtained from the water supply of Hong Kong induce a tumor rate of 20 in Osborne rats exposed by direct application of the dust to the pleural surface For comparison in the same experiments amphibole asbestoses induce tumors at rates ranging from 0 to 100 Wagner 1982 also reported in vivo data on halloysite He observed no mesotheliomas in 40 Fischer 344 rats treated by intrapleural inoculation whereas chrysotile UICC standard B derived from Canadian deposits induces 22.5 mesotheliomas by the same technique Whether the observed difference in the pathogenicities of kaolinite and halloysite is related to particle morphology or other mineralogical properties e.g. surface characteristics is not known In vitro experiments show that kaolinite samples are cytotoxic to most cell types studied though some materials are noncytotoxic Low et al 1980 found that kaolinite is cytotoxic to rabbit alveolar macrophages their sample was a 99 pure kaolinite as determined by XRD and dispersive spectrometry obtained from the Georgia Kaolin Company Davies 1983 showed that kaolinite is also cytotoxic to mouse peritoneal macrophages but that treatment of the dust with vinylpyridine N oxide PVPNO a class of polymers that inhibit the cytotoxicity of quartz Holt et al 1970 almost completely eliminates kaolinite's cytotoxicity Davies noted that his sample contained % mica as determined by XRD Dubes and Mack 1988 found that kaolinite J. T. Baker Chemical Company is 4-5 times more effective than asbestos in mediating transfection of mammalian cell cultures Gormley and Addison 1983 also found that the kaolinite standards of the CMS Clay Mineral Repository KGa and KGa are cytotoxic to a macrophagelike mouse cell line only at high doses In contrast to the above studies however Marks and Nagelschmidt 1959 found that kaolinite is much less cytotoxic to guinea pig peritoneal macrophages than silica minerals Woodworth et al 1982 used the release of Cr to monitor changes in membrane permeability and cell death in Syrian hamster tracheal epithelial cells They found that kaolinite Georgia Kaolin Company will cause the release of Cr Kaolinite is less effective than chrysotile and montmorillonite but more effective than silica There is some indication that kaolinite's cytotoxicity is in part related to broken O bonds at the crystallite edges As noted above Davies 1983 found that the treatment of kaolinite with PVPNO reduces kaolinite's cytotoxicity at amounts less than the total amount of polymer that can be adsorbed implying that only some of the polymer sites may be related to kaolinite s cytotoxic activity Furthermore PVPNO is effective at ^<nhibiting the cytotoxic activity of quartz Holt et al 1970 suggesting that the mechanisms by which quartz and kaolinite exert their cytotoxic effects are related Steel and Anderson 1972 found that the addition of a bacterium Staphylococcus aureus to a kaolinite solution at low NaCl concentrations 14 mM inhibits flocculation possibly because of an interaction between the bacterium and the kaolinite crystal edges Others Kennedy et al 1989 Ghio et al 1990 have shown that kaolinite noncalcined Georgian sample and other pneumoconiosis minerals function as Fenton catalysts electron transfer by Fe = Fe + e- possibly as a result of Fe3 adsorbed on its surface Their studies illus- trate that biochemical mechanisms can be probed effectively if mineral samples are selected carefully Serpentine berthierine and chlorite Chrysotile is the serpentine mineral that has been studied in greatest detail as a potential health hazard As indicated above because of the enormous body of literature on the health effects of chrysotile this mineral is not addressed directly in this paper The interested reader however is directed to the recent article by Mossman et al 1990 and papers by Ross 1981 1984 for reviews of the research on chrys- otile With respect to other serpentine minerals Woodworth et al 1983 found that antigorite Ward's Scientific sample from Arizona does not induce metaplasia proliferation of cells in tracheal mucosa of the golden Syrian hamster in vitro whereas riebeckite asbestos does the tracheal mucosa or lining of the trachea is a part of the respiratory tract with which inhaled dusts interact Using the same material Mossman and Sesko 1990 found that antigorite does not cause the release of stCr from hamster tracheal epithelial cells whereas riebeckite asbestos and chrysotile do Hence if antigorite is cytotoxic it is much less active than chrysotile A berthierine iron ore 40 berthierine sample from Lorraine France and two rich chlorites Pyr^'n^'esand Anjou were studied by Costa et al 1990 using a chemical assay to measure the production of activated species Production of activated species is a mechanism by which a material can induce a toxic response They found that the samples were highly active and they associated this activity with the high Fe content Fe contents reported as FeO were in the range 12.5-30.0 for the three samples but they did not show that the Fe was directly responsible for the observed activity For comparison they found that kaolinite St Austelle and quartz DQ 12 are inactive in the assay Despite the poor quality of the specimens used their study is a good example of the type of mineralogical research that can benefit the field of induced pathogenesis The biochemical mechanisms they investigated with their assay 234 GUTHRIE EFFECTS OF INHALED MINERALS involved an electron process at the mineral sur- face a process similar to many geochemical processes The 2 layer silicates Most studies of samples containing 2 layer silicates suggest that some samples can produce fibrosis in vivo and can be highly active in vitro However epidemiological data suggest that fibrosis may not be a problem in modern mining conditions As with the 1 layer silicates though 2 layer silicates may be cleared rapidly from the lung and hence are not pathogenic in humans their activity may provide clues to the mechanisms of mineralinduced pathogenesis Talc In general epidemiological studies suggest that exposure to bearing dusts elicits a dependent albeit minor response Kleinfeld et al 1967 1974 studied the mortality in a group of 220 talc miners employed for at least 15 yr between 1940 and 1965. Dust exposures in this group were very high before 1945 10 105 particles but dropped substantially after 1945 10 particles furthermore miners were exposed to a variety of dusts including talc serpentine tremolite carbonates and silica During 1945-1959 the mortality rate due to lung cancer was 3.4 times the rate expected based on U.S. white males in 1957 but the rate dropped to near normal during 1960-1969 possibly because of lower exposure levels However because of the exposure to dusts other than talc particularly tremolite it is not possible to assign this effect to talc exposure alone Other studies Selevan et al 1979 Brown and Wagoner 1980 Leophonte and Didier 1990 of talc miners and millers in New England reported similar observations but one study Stille and Tabershaw 1982 found no increases in mortality from lung cancers among workers at one New York mine who had no prior work exposure Coexposure to amphiboles is likely in many studies of exposed workers Cullinan and McDonald 1990 separated seven studies of talc workers on the basis of suspected amphibole exposure Among the three studies with no suspected amphibole exposure no mesotheliomas were reported out of a total of 2540 workers though a slight increase in other respiratory malignancies was observed in two studies Cullinan and McDonald 1990 In vivo experiments on bearing dusts suggest that talc is nonfibrogenic and noncarcinogenic Pott and Friedrichs 1972 observed no fibrosis or abdominal tumors following intraperitoneal injection of talc in Wistar rats In a later experiment using the same technique however Pott et al 1974 observed a slight incidence of tumors 2.5 with a latency period 587 d twice that observed for chrysotile or fibrous brucite Wehner 1980 observed no significant changes in golden Syrian hamsters exposed to talc baby powder presumably obtained from the funding agency Johnson and Johnson hamsters exposed to asbestos cement mineral content not described exhibited a response similar to the talc response at comparable exposures Wehner used asbestos dust mineral content not detailed as a positive control but comparison is hindered because the control experi ments used exposures 8 times those used in the talc ex- periments Stanton et al 1981 observed a statistically insignificant tumor rate in Osborne rats exposed by direct application of talc to the pleural surface Wagner et al 1979 and Wagner 1990 found no lung tumors among 96 Wistar rats exposed to talc by inhalation for 3 1m2onths Their sample contained % impurities including silica chlorite and carbonate Capron et al 1990 induced no pleural tumors after intrapleural injection of mg talc Luzenac France In vitro experiments are inconclusive regarding the cytotoxic activity of bearing dusts Chamberlain and Brown 1978 found that Italian talc commercial cosmetic grade source not given is noncytotoxic to Chinesehamster lung cells at concentrations up to 50 mL However using the same assay Pigott and Pinto 1983 reported that talc source not given is slightly cytotoxic at the same concentration for comparison Pigott and Pinto found that nebeckite asbestos is highly cytotoxiC and calcium carbonate is noncytotoxic Talc is much less hemolytic than kaolinite or montmorillonite Woodworth et al 1982 Brown et al 1980 Despite its weak cytotoxicity talc is an effective mediator in transfection Dubes and Mack 1988 showed that talc talcum powder Mallinckrodt Chemical Works is 2 times more effective than asbestos but ~ times less effective than kaolinite in mediating transfection of mammalian cell cultures Woodworth et al 1982 found that talc Cyprus Industrial Minerals Company Los Angeles will affect cell membrane in hamster tracheal epithelial cells as monitored by the release of Cr Talc is approximately as active as kaolinite in this assay However Endo ron et al 1990 found that talc Luzenac France produces no SCEs in rat pleural mesothelial cells Phlogopite muscovite illite smectite and vermiculite Only a few epidemiological studies of respiratory disease resulting from exposure to dusts containing micas or micalike clays have been published and some of these suggest that such samples can elicit a mild dependent fibrogenic response at high exposure levels e.g. Vestal et al 1943 Exposure to mica minerals is generally accompanied by an exposure to other minerals e.g , silica and amphiboles and the response to these minerals complicates the interpretation of the data e.g. Heimann et al 1953 McDonald et al 1988 For example some cases of vermiculite mesothelioma may be correlated with amphibole contamination see Cullinan and McDonald 1990 for a review of the studies In vivo experiments suggest that samples containing micas or mica clays are slightly fibrogenic King et al 1947 found injection of 50 mg of illite dust separated from shales in southern Wales into the lungs of rats produces no fibrosis unless the clay is pretreated in an HCI solution Policard 1934 used exposure by inhalation to study the short effects 3-30 d of ground white mica from Madagascar light microscopy showed GUTHRIE EFFECTS OF INHALED MINERALS 235 the dust to contain both fibrous and polyhedral particles on the lungs of rats ground white mica induces a cellular response similar to that observed with quartz Pott et al 1974 found that biotite is inactive following intraperitoneal injection in Wistar rats Sykes et al 1982 used intratracheal instillation to study the short < d and medium 100 d effects of bentonite on Alderived rats strain ; specific pathogen free Though these results show that bentonite induces a greater pulmonary response than quartz in the short term medium effects indicate that bentonite induces a response similar to a saline control Rosmanith et al 1990 studied the relationship between surface area and activity using intratracheal installation of a characterized muscovite sample in Wistar rats Rosmanith et al 1990 Schyma 1990 They found that the finest material elicits the greatest fibrogenic response Brambilla et al 1979 reported mild pulmonary lesions in zoo animals exposed to mica dusts Mineralogical analysis of lung contents indicated the presence of muscovite and illite In vitro experiments suggest that samples containing micas and mica clays may be slightly cytotoxic though some studies suggest that phlogopite and montmorillonite may be highly cytotoxic Pigott and Pinto 1983 studied the cytotoxicity of phlogopite hydrophlogopite ? and biotite distinction not explained and muscovite using hamster lung cells All four micas are slightly cytotoxic with muscovite showing the greatest effect and being comparable to talc in activity As mentioned above riebeckite asbestos is highly cyto- toxic in the same study Gormley and Addison 1983 found that samples SAz and STx calcium montmorillonites SWy sodium montmorillonite and SHCa hectorite from the CMS Clay Repository exhibit a range in toxicities with SHCa being slightly cytotoxic roughly comparable to kaolinite samples KGa and KGA and STx being highly cytotoxic more cytotoxic than their positive control quarz It should be noted however that they reported 10 cristobalite in STx as determined by XRD and cristobalite is even more cytotoxic than quartz Marks and Na- gelschmidt 1959 Adamis and Tim^r 1978 used peritoneal macro- phages from Sprague rats to show that both quartz and bentonite Istenmezeje Hungary obtained from Z. Juh^szare cytotoxic but their modes of action are different Although quartz alters the permeability of cell membranes to the enzyme lactate dehydrogenase LDH bentonite does not However bentonite does significant icantly lower the intracellular activity of LDH Costa et al 1990 used a chemical assay to determine the role of Fe2 in the production of activated O species As found for rich chlorite and berthierine rich bi- otite Raz^'sis an effective catalyst in this assay whereas an poor montmorillonite Maroc is an ineffective catalyst In light of the purity of other samples used in the study i.e. iron ore to test berthierine and granite to test biotite and muscovite the mineralogical purity of these specimens may be of some concern Woodworth et al 1982 found that montmorillonite American Colloid Company Skokie Illinois will affect cell membrane in hamster tracheal epithelial cells as monitored by the release of Cr Montmorillonite is roughly as active as chrysotile in this assay However Dubes and Mack 1988 found that bentonite obtained from Fisher Scientific Company is approximately tenth as effective as asbestos at mediating transfec- tion of mammalian cell cultures In contrast Holopainen et al 1990 found that phlogopite phl ann ) is almost twice as hemolytic as quartz and as cytotoxic as quartz to rat alveolar macrophages as determined by the release of LDH After treatment with nitric and sulfuric acids the phlogopite is more hemolytic but less cytotoxic In their assay the hemolytic and cytotoxic activities of muscovite are comparable to those of rutile a negative control Modulated 2 layer silicates Most studies on samples containing modulated 2 layer silicates suggest that some samples can produce fibrosis or tumors in vivo and can be highly active in vitro However epidemiological data suggest these minerals are at most mildly active in humans Sepiolite One epidemiological study suggests that exposure to sepiolite dust does not increase the risk of pulmonary disease Baris et al 1980 studied 63 sepiolite workers in Turkey involved in trimming cleaning and polishing sepiolitic stones Ten of the 63 showed signs of pulmonary fibrosis but no relationship was established between exposure to sepiolite and fibrosis Sputum was analyzed from one of the ten but no ferruginous bodies were observed In vivo experiments by Wagner 1982 using Fischer 344 rats exposed for 1 yr through inhalation showed that sepiolite termed by Wagner as European sepiolite possessing a fibrous morphology is as fibrogenic as riebeckite asbestos However sepiolite induces no mesotheliomas in Fischer 344 rats exposed by intrapleural inoculation whereas chrysotile UICC standard B induces mesotheliomas at a rate of 22.5 Pott et al 1990 found that the response elicited by sepiolite is highly sample dependent The two sepiolite samples studied by Pott et al 1990 showed tumor rates of % Finland and 67 Uicaluaro following intrapleural injection in female Wistar rats Preliminary results of a powder ray diffraction study indicate that these samples contain signifsignificant amounts of other minerals Guthrie and Bish unpublished data quantitative mineral content data are not available yet so it is not possible to correlate purity with biological activity In vitro experiments by Hansen Mossman and co- workers Hansen and Mossman 1987 Mossman et al 1989 indicate that sepiolite Minerals Research is capable of inducing the release of the superoxide anion from both hamster and rat alveolar macrophages in a dose- 236 GUTHRIE EFFECTS OF INHALED MINERALS dependent manner In hamster alveolar macrophages the release induced by sepiolite is comparable to the release induced by erionite and riebeckite asbestos however in rat alveolar macrophages sepiolite is less active than erionite or riebeckite asbestos in eliciting a response Chamberlain et al 1982 found that fiber sepiolite source not given is as cytotoxic as riebeckite asbestos UICC standard to mouse peritoneal rnacrophages as determined by release of LDH and human type II alveolar cells as determined by the formation of giant cells but less cytotoxic than rebeckite asbestos to Chinesehamster lung cells as determined by reduction in cloning efficiency short sepiolite source not given however was determined to be noncytotoxic in the same experiments Palygorskite attapulgite Epidemiological data suggest that exposure to palygorskite dusts may increase the risk of lung cancer among whites Waxweiler et al 1988 Waxweiler et al studied a cohort of 2302 miners and millers from an attapulgite company in the United States They reported SMRs of /1.b0ased on U.S. males for nonmalignant respiratory disease in all races 0.23 0.79 6 0 CI and specific SMRs for lung cancer 1.21-2.93 in whites 90 CI 0.21-1.12 in nonwhites 90 CI Respirable dust exposures were < mg mbut no information concerning mineral content was given except to note that the only fibrous mineral observed is attapulgite clay No mineral content is reported for the dust to which their cohort was exposed Instead reference was made to the typical mineral content of attapulgite clay mined in the United States as reported by Haden and Schwint 1967 a typical dust would thus consist of 70-80 attapulgite 1-15 mont- morillonite sepiolite and other clays 4-8 quartz and 1-5 calcite or dolomite Waxweiler et al 1988 Sors et al 1979 reported a case study of a mining engineer who exhibited signs of respiratory disease following a yr exposure to attapulgite Lung lavage fluids suggested heavy particle burdens XRD gave a pattern similar to those of mineral attapulgite In vivo experiments have suggested that palygorskitebearing dusts are mildly active in the lung though some samples can be very active Stanton et al 1981 showed that attapulgite is slightly tumorigenic in OsborneMendel rats following direct application of the dust to the lungs Experiments using two different samples resulted in tumor rates of 8 -5.3 and 11 -7.5 samples were from Attapulgus Georgia and 9p0 ure the remain- der consisting of quartz Jaurand et al 1987 found that attapulgite French obtained from a deposit in Mormoi- ron is nontumorigenic following intrapleural injection in specific pathogen Sprague rats whereas in the same experiments chrysotile induces tumors at a rate of 19-52 depending on particle size However Wagner 1982 observed mesothelioma rates of 12.5-25 de- pending on specimen preparation method for attapul- gite Spanish following intrapleural inoculation of Fischer 344 rats chrysotile UICC standard B exhibits a comparable mesothelioma rate 22.5 In his inhalation experiments Wagner 1982 showed that attapulgite Spanish is as fibrogenic as rebeckite asbestos but he reported negative results in the two experiments for another attapulgite American B^'ginet al 1987 1990 used a bronchoalveolar lavage technique to monitor the cellular response in lungs of sheep exposed to attapulgite from northern Florida Exposure results in increases in cell numbers and enzyme levels comparable to those observed after similar experiments using the UICC as- bestos standards No fibrosis was observed at the end of the study but the elevated levels of enzymes indicate that the attapulgite is cytotoxic in vivo Coffin et al 1989a reported a 1.4 incidence of mesotheliomas in rats injected intrapleurally with attapulgite from Georgia and Florida compared with a 1.3 incidence in the control group Pott et al 1974 1990 found that attapulgite is carcinogenic at rates from 3.5-40 following intrapleural injection in Wistar rats i.e. the response is sample dependent Preliminary results of a powder ray diffraction study indicate that these samples contain significant amounts of other minerals Guthrie and Bish unpublished data In vitro experiments have indicated that palygorskite is as hemolytic as chrysotile but in other nonerythrocyte cell types palygorskite is at most slightly cytotoxic and is nongenotoxic Bignon et al 1980 showed that attapulgite Spanish was ~ times more hemolytic to human red blood cells than chrysotile UICC standard A derived from Rhodesian deposits Perderiset et al 1989 found that attapulgite Senegalese obtained from Rh^ne Poulenc is hemolytic but that pretreatment of the dust with lipids or proteins material similar to cell membranes or extracellular lung fluid reduces the hemolytic activity Nadeau et al 1983 reported that attapulgite is as hemolytic as chrysotile UICC standard B and more hemolytic than sepiolite or erionite In contrast in vitro experiments using cells other than RBCs have suggested that palygorskite dusts are generally inactive although the activity varies greatly as a function of the surface characteristics of the sample Woodworth et al 1983 found that palygorskite CMS Clay Repository sample from Nevada might have a slight effect on cultured hamster trachea but the effect is not statistically different from the control group riebeckite asbestos and fiber glass however test positive statistically in the same assay Jaurand et al 1987 found that attapulgite French may be cytotoxic to rat pleural mesothelial cells only at high doses whereas chrysotile is generally much more cytotoxic Reiss et al 1980 demonstrated that palygorskite Attapulgus Georgia is much less cytotoxic than amosite asbestos to embryonic intestine epithelial cells Pezerat et al 1989 found that attapulgite Senegalese is inactive in catalyzing the production of O radicals and Achard et al 1987 found that the same material does not induce SCEs in rat pleural mesothelial cells Renier et al 1990 found no unscheduled DNA repair synthesis in rat pleural me- GUTHRIE EFFECTS OF INHALED MINERALS 237 sothelial cells following treatment with attapulgite Mormoiron region France Chamberlain et al 1982 found that fiber attapulgite source not given is more cytotoxic than riebeckite asbestos UICC standard to mouse peritoneal macrophages see description of assays in the section on sepiolite but less cytotoxic than riebeckite asbestos to hamster lung cells shortfiber attapulgite source not given however is slightly cytotoxic to mouse peritoneal macrophages and noncytotoxic to hamster lung cells Nolan et al 1991 further demonstrated that the in vitro activity of palygorskite varies between samples by showing that among nine palygorskites that possess different surface characteristics there is a corresponding range in hemolytic ac- tivity Zeolites The biological activity of erionite has been studied extensively and all data indicate that it is extremely active in humans in vivo and in vitro Data on other zeolites are less conclusive particularly in light of the poor quality of the samples studied Erionite Epidemiological data suggest that exposure to erionite dusts increases the risk of mesothelioma in humans even at much lower exposure levels than required for amphibole asbestos mesothelioma Earlier epidemiological studies in the Cappadocian region of Turkey revealed outbreaks of asbestos respiratory diseases including mesothelioma Baris et al 1979 Initially it was assumed that asbestos present in the stucco used in that region was the cause of these diseases however Baris et al 1979 found outbreaks in villages in which the stucco does not contain asbestos Later studies focused on exposure to erionite as the cause Baris et al 1987 found zeolite fibers as determined by ATEM in air samples from affected villages although air samples from some of these villages additionally contain fibrous tremolite Lung contents as determined from sputum samples S^'bastienet al 1981 1984 identification by ATEM and electron diffraction and biopsies Baris et al 1987 identification by ATEM also indicate that individuals from these regions have been exposed to both erionite and asbestos chrysotile tremolite asbestos and riebeckite asbestos though the amount of zeolite exceeded the combined amounts of asbestos on a fiber basis in the two samples of human lung contents Mumpton 1979 investigated the mineral content of dusts in the Cappadocian region He found that erionite was present in samples from two villages in which mesothelioma rates are high although erionite is abundant only in one of those villages He also found that erionite is abundant in a third village Sarih~-d~-rwhich at that time had no reported cases of mesothelioma Mumpton concluded therefore that the geographic distribution of erionite is inconsistent with the distribution of mesothe- lioma Subsequently however Baris et al 1987 surveyed Sarihidir and reported three cases of mesothelioma Baris et al also reported fiber characteristics from the affected villages indicating that zeolite fibers were present ubiquitously but other types of fibers varied be- tween villages The most disturbing implication of the observations in Turkey is that if erionite is indeed the cause of the high rates of mesothelioma then crionite is capable of inducing mesothelioma in humans at low exposures Baris et al 1987 reported total fiber levels in the villages from 0.004 to 0.175 fibers and these measurements included other dusts in addition to zeolite Simonato et al 1989 reported newer estimates of fiber characteristics in Karain and Sar~-hidirtwo of the affected villages and found levels to be 0.002-0.010 ~ 80 zeolite and 0.0010.029 60 zeolite respectively In vivo experiments have further demonstrated demonstrated the high fibrogenic and carcinogenic potential of erionite dusts Suzuki and Kohyama Suzuki 1982 Suzuki and Kohyama 1984 1988 studied the effects on mice ofin- trapleural injections of two erionite samples one from Needle Peak Nevada Minerals Research listed by Suzuki and Kohyama as Needle Park and one from an unknown locality Resource International Company In mice injected intrapleurally with 2 mg of dust Needle Peak erionite induces tumors at a rate of 54 % compared with 0-25 for chrysotile and 40 % for amosite asbestos fibrosis also develops after injection of any of the dusts They also performed experiments using higher doses but a low percentage of mice survived long enough to develop tumors > months Maltoni et al 1982 are investigating the effect of method of exposure to erionite on the induction of mesotheliomas in rats For their in1- tial results they reported that erionite sedimentary obtained from G. Gottardi University of Modena Italy induces mesotheliomas by intrapleural injection at a rate of 90 nine of ten rats whereas riebeckite asbestos induces mesothelioma by intraperitoneal injection at a rate of 100 12 of 12 Wagner and coworkers have also studied the in vivo effects of exposure to erionite using specific pathogen Sprague rats Wagner 1982 and Fischer 344 rats Wagner et al 1985 They used intrapleural injection 20 mg and inhalation to study the carcinogenic potential of four erionite samples Oregonian erionite from F. Mumpton Minerals Research nonfibrous synthetic zeolite chemically identical to erionite from R. Taylor Laporte Industries a New Zealand erionite similar size distribution to the Oregonian sample though fibers are slightly thicker and a Turkish Karain rock determined to consist of poorly consolidated rock . made of incompletely formed erionite . in an amorphous matrix which has the same composition as erionite Wagner et al 1985 In the rats intrapleurally injected with Oregonian erionite and Turkish rock 40 of 40 and 38 of 40 developed mesotheliomas respectively with mean survival times of 390 and 435 d the New Zealand erionite was ... as potent as the Oregonian and Turkish enonites For comparison in the same experiment chrysotile induced 19 mesotheliomas in 40 rats with a mean sur- 238 GUTHRIE EFFECTS OF INHALED MINERALS vival time of 678 d The same effect was observed in the inhalation experiments 27 of 28 rats exposed to Orego- nian erionite developed mesotheliomas with a mean survival time of 580 d compared with one of 28 rats exposed to riebeckite asbestos UICC standard with a mean survival time of 917 d The synthetic zeolite was also tested in the inhalation experiments and induced two tumors in 28 rats with a mean survival time of 784 d With respect to the erionite sample they stated No other dusts we have investigated have produced this high incidence of tumours particularly following inhalation Wagner et al 1985 Coffin et al 1989a confirmed the observation that erionite rats develop mesotheliomas at a higher rate and in a shorter time than chrysotile asbestosor riebeckite asbestos rats the erionite used was from Rome Oregon Minerals Research and was prepared by either H sOedimentation or air elutriation In two later studies the Wagner group confirmed their original finding Johnson and Wagner 1989 exposed Fischer 344 rats to erionite from Rome Oregon obtained from Minerals Research by inhalation in a dust environment 10 mg and found that erionite exposure produces both fibrosis and mesothelioma three of the three rats exposed to dust for 12 weeks and allowed to recover for 12 months developed mesothelioma Hill et al 1990 used intrapleural injection of Oregonian erionite in Porton rats to determine the response relationship for induction of mesotheliomas They found a sharp rise in mesothelioma rate from % mesotheliomas at 0.01 mg to 90 at 1.0 mg they stated erionite is over 200 times more tumourogenic than crocido- lite In vitro studies have demonstrated that erionite ing dusts are both cytotoxic and genotoxic Poole et al 1983b studied the genotoxic effects of Oregonian erionite Minerals Research by monitoring morphological transformations and unscheduled DNA repair in mouseembryo fibroblasts cells that reside in the connective tissue and that are responsible for collagen production i.e. that are involved in fibrosis Erionite was found to be active in both of these tests whereas amphibole asbestos does not cause morphological transformations Poole et al 1983a Numerous studies have also demonstrated that erionite is cytotoxic Palekar et al 1988 Brown et al 1989 and genotoxic Palekar et al 1987 1989a 1989b to hamster lung cells Brown et al 1989 found that the cytotoxic effects are related to long thin fibers since milling of the sample to reduce the fiber lengths also reduces its activity The cytotoxic and genotoxic activities of erionite are slightly less than those of asbestos when compared on a mass basis but comparison on a fiber basis shows that the activities of erionite are much greater than those of asbestos Palekar et al 1988 Brown et al 1989 In other tests for genotoxicity Hansen Mossman and coworkers Hansen and Mossman 1987 Mossman et al 1989 Mossman and Sesko 1990 have shown that erionite Rome Oregon from R. Davies is as effective as riebeckite asbestos in catalyzing the production of the superoxide anion from hamster and rat alveolar macro- phages In contrast however Pezerat et al 1989 found that though Oregonian erionite is nearly as effective as most types of asbestos at catalyzing the production of O radicals from an aqueous medium it is inactive when compared with chrysotile UICC standard B or fibrous brucite Kelsey et al 1986 found that erionite Rome Oregon obtained from V. Timbrell induces SCEs slightly in hamster ovary cells whereas rebeckite asbestos UICC standard does not ultraviolet light however is much more effective at inducing SCEs Both Oregonian erionite and rebeckite asbestos UICC standard induce low levels of chromosomal aberrations in the hamster ovary cells Kelsey et al 1986 Coffin et al are attempting to relate the biological activity of erionite to its mineralogical characteristics Coffin et al 1989b Mordenite and other zeolites In vivo experiments by Suzuki and Kohyama Suzuki 1982 Suzuki and Kohyama 1984 1988 suggest that a mordenite dust and zeolite 4A are fibrogenic but noncarcinogenic Suzuki and Kohyama used intraperitoneal injection in mice to test the biological response to various zeolites Included in their experiments was a mordenite sample Resource International Company Denver that contained both granular and fibrous morphologies and a synthetic zeolite 4A Union Carbide Corporation quant~-tative ray diffraction of the mordenite sample has shown that it contains 63.5 impurities including clinoptilolite feldspar opal and gypsum Guthrie and Bish unpublished data In fact mordenite was used in these experiments to test the relationship between particle shape and activity among zeolites The mordenite sample was described as a mixture of fibrous and nonfibrous forms despite the fact that mordenite is uniquely fibrous Hence it should be recognized that their results apply to an impure mordenite sample Their experiments show that mg doses of either the mordenite sample or zeolite 4A induce no tumors in mice for experiments up to 23 months in duration fibrosis however does result from the exposure On the other hand the same experiments showed that 0.5- and 20 mg doses of erionite Needle Peak Nevada induce tumors at 33 and 54.5 respectively also fibrosis in exposed mice is more pronounced In their group exposed to a 10mg dose of erionite a 37.5 rate of tumor induction was observed but only eight rats survived to > months e exposure to erionite may elicit a dependent response in the lungs of mice but this relationship cannot be tested because of the poor statistical significance of the results from the group exposed to high concentrations of erionite Malton~-and M~-nard~1- 988 1989 studied the biological activity of synthetic zeolites used in detergents MS 4A and MS 5A Na and Ca rich respectively source not given by intraperitoneal intrapleural and subcutaneous injection in rats For both zeolites and all routes of ex- GUTHRIE EFFECTS OF INHALED MINERALS 239 posure tumors appeared but not at rates significantly dif- ferent from those observed in the control groups that were injected with H 2 O 5 5In0the same assay how- ever riebeckite asbestos induces tumors following injec- tion into the abdominal cavity at a rate of 97.5 In vitro experiments suggest that mordenite dust is much less active than erionite Hansen Mossman and coworkers Hansen and Mossman 1987 Mossman et al 1989 Mossman and Sesko 1990 found that a mordenite sample source not given is less effective than sepiolite and much less effective than erionite at stimulating the release of the superoxide anion from rat alveolar macrophages Palekar et al 1988 found that this same mordenite is noncytotoxic to hamster lung cells Quantitative ray diffraction of this mordenbearing sample has shown that it contains 50.5 impurities including clinoptilolite feldspar and opal Guthrie and Bish unpublished data As was the case for the in vivo experiments of Suzuki and Kohyama mor- denite was used as a nonfibrous control in the in vitro assays despite that mordenite is uniquely fibrous Rom et al 1983 discussed the implications of fibrous zeolite health hazards with respect to the western United States and stressed the need for epidemiological studies in this region Table 2. Summary of data on the biological activities of clays and zeolites Mineral Hematite Goethite Lepidocrocite Boehmite Fibrous brucite Kaolinite Halloysite Antigorite Berthierine Chlorite rich Talc mica clays Sepiolite Palygorskite Erionite Mordenite Zeolites 4A and 5A Epidemio logical - n.d n.d nd n.d + f n.d n.d n.d n.d. to + f - to +++ nd nd In vivo ~ + to ++ 3333333 + 3333333 + to ++ 3333333 ++ 3333333 +++ 3333333 ++ 3333333 - to 3333333 n.d n.d n.d 1 to f +++ f 111 t +++ f to t +++ f +++ t + f - {t) + (f) t In vitro - nd nd nd ++ +++ n.d - +++ +++ +++ to +++ +++ +++ to nd Note Symbols indicates inactive + indicates active nd indicates no data available f and t indicate fibrogenic and tumorigenic respectively DISCUSSION The wide range of minerals that have been studied by various techniques offers the potential for revealing the causes of a mineral's biological activity Indeed it is clear from the dusts studied already that minerals exhibit different activities and elicit different biological responses Table 2 In fact differences in biological response can be found both between mineral species and between different samples of the same mineral species The variations in response likely reflect variations in the interactions between the mineral surfaces and biological components 1.e. cell surfaces enzymes proteins DNA etc. Ideally if this observed variation can be related to differences in the physical and chemical properties of the minerals then the mechanisms of mineral toxicity may be elucidated Unfortunately several mineralogical prob- lems are present in the studies reviewed above that make such inferences difficult if not impossible Generally the primary mineralogical aspects that are controlled in most biological experiments are the particle shape and size distribution and mass concentration or dose employed since these parameters appear to relate to the material's bio- logical activity as determined by in vivo methods e.g. Stanton et al 1981 The exact mineral content of the dusts however is rarely characterized In other words little attention is generally given to the identification and amount of contaminants in the dust sample Instead it is assumed that the mineral content of the sample matches the information provided by the supplier However samples obtained from most suppliers potentially contain a mixture of minerals and often are simply a different mineral from the one listed on the label The mordenite samples used in both the in vitro experiments Hansen and Mossman 1987 Palekar et al 1988 Mossman et al 1989 Mossman and Sesko 1990 and the in vivo experiments Suzuki 1982 Suzuki and Kohyama 1984 1988 illustrate this well Each sample actually contains a mixture of mordenite clinoptilolite feldspar opal and gypsum Guthrie and Bish unpublished data The published mordenite data actually apply to a mixture of minerals that is /5m0 ordenite Another mineralogical problem in biological studies is that the surface properties of the samples are generally not adequately characterized Recent work e.g. Pezerat 1990 has suggested that although the fibrous shape of a material may be important in maintaining the particle in the target organ or in enhancing surface area the mechanisms by which minerals are toxic relate to their surface properties such as active oxidation sites Indeed the activity of a mineral varies with surface state Nolan et al 1991 and surface area Gormley and Addison 1983 which in turn can vary substantially between samples Thus it is not only important to control the surface aspects of a mineral during an experiment but it is important to characterize these properties so that they can be related to biological activity These mineralogical deficiencies in biomedical research can be rectified through collaborative efforts be- tween minerals scientists and health scientists Such col- laboration should involve both characterization of the mineralogical aspects of the experiment and design of experiments that will allow mechanistic questions to be addressed For example an amphibole has numerous prop- 240 GUTHRIE EFFECTS OF INHALED MINERALS erties that might contribute to its activity e.g. broken Si bonds exchangeable cations in the A site poly- valent cations in the octahedral sites underbonded O resulting from Al substitution in the tetrahedral sites specific surface periodicities Hence the results of a study on amphibole pathogenesis may record effects from several mineralogical properties On the other hand it is possible to isolate the effects of a specific mineralogical characteristic by an appropriate choice of mineral pairs For instance the role of polyvalent cations in the octahedral site can be determined by comparing the activities between two minerals that differ only in the composition of the octahedral site e.g. tremolite and ferroactinolite annite and phlogopite This type of approach could be extremely effective for determining mineralogical mechanisms of induced pathogenesis Such information will lead to both a better understanding of diseases such as cancer and more effective regulation of minerals since regulations can be based on mineralogical properties additional to particle size and shape Furthermore it should be recognized that though a mineral is active in a particular assay it may pose limited risk to humans A complete understanding of the numerous factors that contribute to induced pathogen- esis is essential before the results of any one assay can be used to predict risk to humans ACKNOWLEDGMENTS I would like to thank D.L. Bish G.D. Guthrie Sr. and C.S. NicholsonGuthrie for extensive discussions and encouragement during the preparation of this manuscript I also benefited from discussions with F. Mumpton and B. Lehnert Thoughtful reviews of the manuscript were provided by D.L Bish J. Hughes B. Lehnert W Moll BT Mossman M. Ross and D. Van~-manMy time was supported by a postdoctoral fellowship from the Director's office at the Los Alamos National Laboratory REFERENCES CITED Achard S. 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