Excitable systems: A new perspective on the cellular impact of elongate mineral particles.

We investigate how the geometry of elongate mineral particles (EMPs) in contact with cells influences esotaxis, a recently discovered mechanism of texture sensing. Esotaxis is based on cytoskeletal waves and oscillations that are nucleated, shaped, and steered by the texture of the surroundings. We find that all EMPs studied trigger an esotactic response in macrophages, and that this response dominates cytoskeletal activity in these immune cells. In contrast, epithelial cells show little to no esotactic response to the EMPs. These results are consistent with the distinct interactions of both cell types with ridged nanotopographies of dimensions comparable to those of asbestiform EMPs. Our findings raise the question of whether narrow, asbestiform EMPs may also dominate cytoskeletal activity in other types of immune cells that exhibit similar esotactic effects. These findings, together with prior studies of esotaxis, lead us to the hypothesis that asbestiform EMPs suppress the migration of immune cells and activate immune signaling, thereby outcompeting signals that would normally stimulate the immune system in nearby tissue.

Dimensions of elongate mineral particles and cancer: A review.

CONTEXT: Based on a decade-long exploration, dimensions of elongate mineral particles are implicated as a pivotal component of their carcinogenic potency. This paper summarizes current understanding of the discovered relationships and their importance to the protection of public health. OBJECTIVES: To demonstrate the relationships between cancer risk and dimensions (length, width, and other derivative characteristics) of mineral fibers by comparing the results and conclusions of previously published studies with newly published information. METHODS: A database including 59 datasets comprising 341,949 records were utilized to characterize dimensions of elongate particles. The descriptive statistics, correlation and regression analysis, combined with Monte Carlo simulation, were used to select dimensional characteristics most relevant for mesothelioma and lung cancer risk prediction. RESULTS: The highest correlation between mesothelioma potency factor and weight fraction of size categories is achieved for fibers with lengths >5.6 µm and widths ≤0.26 µm (R = 0.94, P < 0.02); no statistically significant potency was found for lengths <5 µm. These results are consistent with early published estimations, though are derived from a different approach. For combinations of amphiboles and chrysotile (with a consideration of a correction factor between mineral classes), the potency factors correlated most highly with a fraction of fibers longer than 5 µm and thinner than 0.2 µm for mesothelioma, and longer than 5 µm and thinner than 0.3 µm for lung cancer. Because the proportion of long, thin particles in asbestiform vs. non-asbestiform dusts is higher, the cancer potencies of the former are predicted at a significantly higher level. The analysis of particle dimensionality in human lung burden demonstrates positive selection for thinner fibers (especially for amosite and crocidolite) and prevailing fraction of asbestiform habit. CONCLUSION: Dimensions of mineral fibers can be confirmed as one of the main drivers of their carcinogenicity. The width of fibers emerges as a primary potency predictor, and fibers of all widths with lengths shorter than 5 µm seem to be non-impactful for cancer risk. The mineral dust with a fibrous component is primarily carcinogenic if it contains amphibole fibers longer than 5 µm and thinner than 0.25 µm.

Elongate mineral particles (EMP) characteristics and mesothelioma: Summary and resolution for session I of the Monticello II conference.

The summary contains a consensus opinion regarding the current state of the science about the dimensions of Elongate Mineral Particles (EMPs) as a factor impacting their carcinogenicity.

An updated review of diffuse mesothelioma of the pleura - A sentinel health event of potential elongate mineral particle pathogenicity.

There are approximately 400 inorganic minerals in the Earth's crust, some of which can be encountered as elongate mineral particles [EMPs] with dimensional characteristics similar to the six minerals known as asbestos and other asbestiform amphiboles with established human pathogenicity. In addition, the rapidly developing field of nanotechnology is producing an ever-increasing array of high aspect ratio engineered nanomaterials [HARNs] with physical dimensions and biodurability similar to the asbestos fiber types with recognized pathogenic potential. Many of these non-asbestos/non-asbestiform EMPs and HARNs with the potential for aerosolization into the breathing zones of workers and in individuals in non-occupational environments have not yet been thoroughly studied with respect to their potential human pathogenicity, a fact which obviously poses concerns for both occupational health and public health professionals. On the basis of dose-response considerations it seems reasonable to infer that if any of these non-regulated EMPs or HARNs actually are pathogenic, then those mineral fiber exposure-induced disorders associated with the lowest cumulative exposure doses of the commercial amphibole types of asbestos, that is, diffuse mesothelioma of the pleura, and its non-malignant correlate of benign parietal pleural plaques, are those which are most likely to occur following inhalational exposures to any of the non-regulated EMPs and HARNs. Because of that observation, this paper reviews certain aspects of diffuse mesothelioma, including a summary of recent changes in the nomenclature of diffuse mesothelioma of the pleura; of both the descriptive and the analytical epidemiology of the disease; of the etiologies of mesothelioma, both "exposure" related and endogenous in nature; and of the asbestos population attributable fraction for diffuse mesotheliomas in the USA, both historically and in the future.

Toxicological and epidemiological approaches to carcinogenic potency modeling for mixed mineral fiber exposure: the case of fibrous balangeroite and chrysotile.

CONTEXT: Excess mesothelioma risk was observed among chrysotile miners and millers in Balangero, Italy. The mineral balangeroite has been identified in an asbestiform habit from the Balangero chrysotile mine (Italy). Previous studies did not contain a detailed description of the fiber dimensions, thus limiting possible approaches to estimating their carcinogenic potential. OBJECTIVES: To reconstruct excess mesothelioma risk based on characteristics of mixed fiber exposure. METHODS: The lengths and widths of particles from a sample of balangeroite were measured by transmission electron microscopy (TEM). Statistical analysis and modeling were applied to assess the toxicological potential of balangeroite. RESULTS: Balangeroite fibers are characterized as asbestiform, with geometric mean length of 10 µm, width of 0.54 µm, aspect ratio of 19, and specific surface area of 13.8 (1/µm). Proximity analysis shows dimensional characteristics of balangeroite close to asbestiform anthophyllite. Modeling estimates the average potency of balangeroite as 0.04% (95% CI 0.0058, 0.16) based on dimensional characteristics and 0.05% (95% CI-0.04, 0.24) based on epidemiological data. The available estimate of the fraction of balangeroite in the Balangero mine is very approximate. There were no data for airborne balangeroite fibers from the Balangero mine and no lung burden data are available. All estimates were performed using weight fractions of balangeroite and chrysotile. However, based on reasonable assumptions, of the seven cases of mesothelioma in the cohort, about three cases (43%) can be attributed to fibrous balangeroite. CONCLUSION: The presence of different types of mineral fibers in aerosolized materials even in small proportions can explain observed cancer risks.

Dimensional characteristics of the major types of amphibole mineral particles and the implications for carcinogenic risk assessment.

Context: Though some significant advances have been made in recent decades to evaluate the importance of size and morphology (habit) of elongate mineral particles (EMPs), further research is needed to better understand the role of each dimensional metric in determining the levels of cancer potency.Objective: To determine dimensional parameters most relevant for predicting cancer potency of durable elongate particles, specifically amphibole and durable silicate minerals generally.Methods: A database on dimensional and other relevant characteristics of elongate amphibole mineral particles was created, containing particle-by-particle information for 128 099 particles. Integral statistical characteristics on dimensionality of various amphibole types and morphological habits of EMPs were calculated, compared, and correlated with published mesothelioma and lung cancer potency factors.Results: The highest absolute Pearson correlation (r = 0.97, r2 = 0.94, p < 0.05) was achieved between mesothelioma potency (RM) and specific surface area. The highest correlation with adjusted lung cancer potency was found with particle aspect ratio (AR) (r = 0.80, r2 = 0.64, p < 0.05). Cluster analysis demonstrates that fractions of thin fibers (width less than 0.15 and 0.25 µm) also closely relate both to lung cancer and RM. Asbestiform and non-asbestiform populations of amphiboles significantly differ by dimensionality and carcinogenic potency.Conclusions: Dimensional parameters and morphological habits of EMPs are the main drivers for the observable difference in cancer potency among amphibole populations.

Dimensional determinants for the carcinogenic potency of elongate amphibole particles.

CONTEXT: Carcinogenic properties of particulates depend, among other factors, on dimensional characteristics that affect their ability to reach sensitive tissue, to be removed or retained, and to interact with the cells. OBJECTIVE: To model mesothelioma and lung cancer potency of amphibole particles based on their dimensional characteristics and mineral habit (asbestiform vs. nonasbestiform) utilizing epidemiological data and detailed size information. METHODS: The datasets from recently created depository of dimensional information of elongate mineral particles were used to correlate mesothelioma and lung cancer potency with the fraction of particles in a specific size range and the ratio of length and width in different powers. In addition, the cancer potency factors were estimated and compared for 30 asbestiform, 15 nonasbestiform, and 10 mixed datasets. RESULTS: For particles longer than 5 µm, the highest correlation with mesothelioma potency was achieved for width <0.22 µm, and with lung cancer <0.28 µm. The statistical power of the correlation was observed to lose significance at a maximum width of 0.6-0.7 µm. Mesothelioma potency correlated with length in the power of 1.9 divided by width in the power of 2.97, lung cancer potency with length in the power of 0.4 divided by width in the power of 1.17. The predicted cancer potencies of asbestiform, nonasbestiform, and mixed categories were significantly different. CONCLUSION: While additional studies in this direction are warranted, this paper should serve as an additional confirmation for the role of fiber dimensions in the carcinogenicity of amphibole elongate mineral particles (EMPs).

Integration of Evidence on Community Cancer Risks from Elongate Mineral Particles in Silver Bay, Minnesota.

The potential for cancer-related risks to community members from ambient exposure to elongate mineral particles (EMPs) in taconite processing has not been formally evaluated. We evaluated 926 ambient air samples including 12,928 EMPs (particle structures with length-to-width ratio ≥3:1) collected over 26 years near a taconite processing facility in Silver Bay, Minnesota. Eighty-two percent of EMPs were ≤3 µm in length and 97% of EMPs had an average aspect ratio <20:1. A total of 935 (7.3%) EMPs had length >5 µm and AR ≥3:1. Average ambient concentration of NIOSH countable amphibole EMPs over all years was 0.000387 EMPs per cubic centimeter (EMP/cm3 ). Of 12,765 nonchrysotile EMPs, the number of amphiboles with length and width dimensions that correlate best with asbestos-related carcinogenicity ranged from four (0.03%) to 13 (0.1%) and the associated ambient amphibole air concentrations ranged from 0.000003 to 0.000007 EMP/cm3 . After 65 years of taconite processing in Silver Bay, evidence of an increased risk of mesothelioma and lung cancer in community members who did not work in the taconite industry is lacking. The absence of an increased risk of asbestos-related cancer in the Silver Bay community is coherent with supporting evidence from epidemiological and toxicological studies, as well as ambient exposure data and lake sediment data collected in Minnesota Iron Range communities. Collectively, the data provide consistent evidence that nonasbestiform amphibole minerals lack the carcinogenic potential exhibited by amphibole asbestos.

Aerodynamic size separation of glass fiber aerosols.

The objective of this study was to investigate the efficacy of an aerodynamic separation scheme for obtaining aerosols with nearly monodisperse fiber lengths as test samples for mechanistic toxicological evaluations. The approach involved the separation of aerosolized glass fibers using an Aerodynamic Aerosol Classifier (AAC) or a multi-cyclone sampling array, followed by the collection of separated samples on filter substrates, and the measurement of each sample fiber length distribution. A glass fiber aerosol with a narrow range of aerodynamic sizes was selected and sampled with the AAC or multi-cyclone sampling array in two separate setups. The fiber length and diameter were measured using a field emission scanning electron microscope. The glass fiber aerosol was separated in distinct groups of eight with the AAC and of four with the multi-cyclone sampling array. The geometric standard deviations of the fiber length distributions of the separated aerosols ranged from 1.49 to 1.69 for the AAC and from 1.6 to 1.8 for multi-cyclone sampling array. While the separation of glass fiber aerosols with an AAC is likely to produce two different length fiber groups and the length resolution may be acceptable, the overall mass throughput of these separation schemes is limited.

A comparison of asbestos fiber potency and elongate mineral particle (EMP) potency for mesothelioma in humans.

Dr. Garabrant presented a paper concerning a comparison of asbestos fiber potency and elongate mineral particle (EMP) potency for mesothelioma in humans at the Elongate Mineral Particles Conference in Charlottesville, Virginia in 2017. I was a participant at the Conference. Following Dr. Garabrant's talk, I rose in question period to point out that he had not considered information about the occurrence of mesothelioma in several cohorts that was published after the studies that he cited. These additional data were still not addressed in the paper published in your Journal. I believe that your readers would be interested in these, so this letter is written to draw the additional data to their attention.

Reconstructing historical exposures to elongate mineral particles (EMPs) in the taconite mining industry for 1955-2010.

As part of ongoing epidemiological studies for assessing the association between exposure to dust from taconite operations and the development of respiratory diseases, the goal of this study was to reconstruct the exposures of workers to elongate mineral particle (EMP) in the Minnesota taconite mining industry from 1955-2010. Historical NIOSH-7400 and equivalent EMP personal exposure data were extracted from two sources: (1) the Mine Safety and Health Administration (MSHA) online database recorded for all inspection results since 1978 with 655 EMP monitoring records from 1978-2010 for 13 MSHA Mine IDs associated with this study; and (2) the mining companies' internal monitoring reports contained 96 personal EMP exposure records. NIOSH-7400 EMP personal exposures were measured for workers in different jobs in all active mines in 2010 by obtaining 1,285 personal samples. After data treatment, all data were grouped into seven mines and eight departments. Within each mine-department, the yearly EMP mean concentration in f/cc for each year of operation was predicted using two approaches. The performance of two approaches varied by situation. The assumptions underlying each approach described in this article have limitations. A linear regression based on limited historical measurements and those made in 2010-2011 (Approach 1) does not yield reasonable and plausible values of the slope. Approach 2 assumes that the EMP and the respirable dust in the same department share the same historical time trend. This approach allowed us to avail of the more reasonable slope estimates from the historical respirable dust data set and yielded more plausible historical exposure estimates for most locations. This work with two different job exposure matrix (JEMs) provides a unique research opportunity to study the potential impact of exposure assessment to epidemiological results. Both JEMs are being used to assess associations between EMP and respiratory disease in epidemiological studies.

A comparison of asbestos fiber potency and elongate mineral particle (EMP) potency for mesothelioma in humans.

We analyzed the mesothelioma mortality in cohorts of workers exposed to crocidolite, amosite, and chrysotile to estimate asbestos fiber potency for mesothelioma, using the method of Hodgson and Darnton (2000). We relied on the original 17 cohort studies in their analysis, along with 3 updates of those studies and 3 new asbestos cohort studies published since 2000. We extended the analyses to examine the mesothelioma potency of tremolite in vermiculite from Libby, Montana, and for non-asbestiform elongate mineral particles (EMPs) in taconite iron ore, talc, and South Dakota gold mining. Mesothelioma potency (RMeso) was calculated as the percent of all expected deaths that were due to mesothelioma per fiber/cc-year of exposure.The RMeso was 0.0012 for chrysotile, 0.099 for amosite, and 0.451 for crocidolite: thus, the relative potency of chrysotile:amosite:crocidolite was 1:83:376, which was not appreciably different from the estimates by Hodgson and Darnton in 2000. The RMeso for taconite mining fibers was 0.069 which was slightly smaller than that for amosite. The RMeso for Libby fibers was 0.028 which was greater than that for chrysotile and less than that for amosite. Talc and gold mining EMPs were non-potent for mesothelioma. Although there are a number of methods for estimating fiber potency of asbestos and non-asbestiform EMPs, the method of Hodgson and Darnton provides a uniform method by which fiber potency can be compared across many fiber types. Our estimates of RMeso provide a useful addition to our knowledge of mesothelioma potency for different asbestos and non-asbestiform EMP fibers.

Dosimetry of inhaled elongate mineral particles in the respiratory tract: The impact of shape factor.

Inhalation exposure to some types of fibers (e.g., asbestos) is well known to be associated with respiratory diseases and conditions such as pleural plaques, fibrosis, asbestosis, lung cancer, and mesothelioma. In recent years, attention has expanded to other types of elongate mineral particles (EMPs) that may share similar geometry with asbestos fibers but which may differ in mineralogy. Inhalability, dimensions and orientation, and density are major determinants of the aerodynamic behavior for fibers and other EMPs; and the resultant internal dose is recognized as being the critical link between exposure and pathogenesis. Insufficient data are available to fully understand the role of specific physicochemical properties on the potential toxicity across various types of fiber materials. While additional information is required to assess the potential health hazards of EMPs, dosimetry models are currently available to estimate the initially deposited internal dose, which is an essential step in linking airborne exposures to potential health risks. Based on dosimetry model simulations, the inhalability and internal dose of EMPs were found to be greater than that of spherical particles having the same mass or volume. However, the complexity of the dependence of internal dose on EMPs dimensions prevented a straightforward formulation of the deposition-dimension (length or diameter) relationship. Because health outcome is generally related to internal dose, consideration of the factors that influence internal dose is important in assessing the potential health hazards of airborne EMPs.

Pleural abnormalities and exposure to elongate mineral particles in Minnesota iron ore (taconite) workers.

BACKGROUND: Iron ore (taconite) mining and processing are an important industry in northern Minnesota and western Michigan. Concerns around exposures have centered largely on exposure to non-asbestiform amphibole elongate mineral particles (EMPs) found in the eastern portion of the Minnesota iron range. METHODS: A cross sectional survey was undertaken of current and former taconite workers and spouses along with a detailed exposure assessment. Participants provided an occupational history and had a chest radiograph performed. RESULTS: A total of 1188 workers participated. Potential exposures to non-amphibole EMPs were evident across multiple jobs in all active mines. Pleural abnormalities were found in 16.8% of workers. There was an association of pleural abnormalities with cumulative EMP exposure that was not specific to the eastern portion of the range. CONCLUSION: There was evidence of a mild to moderate increase in pleural abnormalities in this population of miners, associated with geographically non-specific cumulative EMP exposure.

The relationship between various exposure metrics for elongate mineral particles (EMP) in the taconite mining and processing industry.

Different dimensions of elongate mineral particles (EMP) have been proposed as being relevant to respiratory health end-points such as mesothelioma and lung cancer. In this article, a methodology for converting personal EMP exposures measured using the National Institute for Occupational Safety and Health (NIOSH) 7400/7402 methods to exposures based on other size-based definitions has been proposed and illustrated. Area monitoring for EMP in the taconite mines in Minnesota's Mesabi Iron Range was conducted using a Micro Orifice Uniform Deposit Impactor (MOUDI) size-fractionating sampler. EMP on stages of the MOUDI were counted and sized according to each EMP definition using an indirect-transfer transmission electron microscopy (ISO Method 13794). EMP were identified using energy-dispersive x-ray and electron diffraction analysis. Conversion factors between the EMP counts based on different definitions were estimated using (1) a linear regression model across all locations and (2) a location-specific ratio of the count based on each EMP definition to the NIOSH 7400/7402 count. The highest fractions of EMP concentrations were found for EMP that were 1-3 µm in length and 0.2-0.5 µm in width. Therefore, the current standard NIOSH Method 7400, which only counts EMP >5 µm in length and ≥ 3 in aspect ratio, may underestimate amphibole EMP exposures. At the same time, there was a high degree of correlation between the exposures estimated according to the different size-based metrics. Therefore, the various dimensional definitions probably do not result in different dose-response relationships in epidemiological analyses. Given the high degree of correlation between the various metrics, a result consistent with prior research, a more reasonable metric might be the measurement of all EMP irrespective of size. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: figures detailing EMP concentration.].

Comprehensive assessment of exposures to elongate mineral particles in the taconite mining industry.

Since the 1970s, concerns have been raised about elevated rates of mesothelioma in the vicinity of the taconite mines in the Mesabi Iron Range. However, insufficient quantitative exposure data have hampered investigations of the relationship between cumulative exposures to elongate mineral particles (EMP) in taconite dust and adverse health effects. Specifically, no research on exposure to taconite dust, which includes EMP, has been conducted since 1990. This article describes a comprehensive assessment of present-day exposures to total and amphibole EMP in the taconite mining industry. Similar exposure groups (SEGs) were established to assess present-day exposure levels and buttress the sparse historical data. Personal samples were collected to assess the present-day levels of worker exposures to EMP at six mines in the Mesabi Iron Range. The samples were analyzed using National Institute for Occupational Safety and Health (NIOSH) methods 7400 and 7402. For many SEGs in several mines, the exposure levels of total EMP were higher than the NIOSH Recommended Exposure Limit (REL). However, the total EMP classification includes not only the asbestiform EMP and their non-asbestiform mineral analogs but also other minerals because the NIOSH 7400 cannot differentiate between these. The concentrations of amphibole EMP were well controlled across all mines and were much lower than the concentrations of total EMP, indicating that amphibole EMP are not major components of taconite EMP. The levels are also well below the NIOSH REL of 0.1 EMP cc(-1). Two different approaches were used to evaluate the variability of exposure between SEGs, between workers, and within workers. The related constructs of contrast and homogeneity were calculated to characterize the SEGs. Contrast, which is a ratio of between-SEG variability to the sum of between-SEG and between-worker variability, provides an overall measure of whether there are distinctions between the SEGs. Homogeneity, which is the ratio of the within-worker variance component to the sum of the between-worker and within-worker variance components, provides an overall measure of how similar exposures are for workers within an SEG. Using these constructs, it was determined that the SEGs are formed well enough when grouped by mine for both total and amphibole EMP to be used for epidemiological analysis.

Letter to the Editor: Epidemiology holds a key to the validation of toxicological models for elongate mineral particles.

The authors reply to the comments of Drs. Gualtieri and di Giuseppe on the short communication by Wylie and Korchevskiy - Carcinogenicity of fibrous glaucophane: how to fill data gaps? (2021 Current Research in Toxicology Volume 2, pp. 202-203). The role of epidemiology in establishing the toxicity of elongate mineral particles is emphasized. The validation of quantitative structure-activity relationship (QSAR) models by disease outcome is mentioned as one of the most important tools in advancing the new approaches in mineral particle toxicology.

Size Separation of Amosite by Filtration and Shaking Methods.

The objectives of this study are (1) to separate fibrous grunerite (amosite) by its length using filtration and shaking techniques utilized in a previous study and (2) to create two distinct length groups (short and long) of the amosite with higher output in a cost-effective way. The shaking system included an electrodynamic exciter, a linear power amplifier, and an audio-frequency signal generator and was attached to a cowl sampler as a funnel loaded with a polycarbonate filter. A suspension of amosite was passed through the 10-µm pore size polycarbonate filter in the shaking system and was transferred to a filtration system through five different pore sizes of polycarbonate membrane filters in series from the top: 10-, 5-, 2-, 1-, and 0.2-µm pore sizes. Each polycarbonate filter was tightly clamped with two conductive 25-mm spacers with a 25-mm stainless steel support screen to prevent leakage. The amosite length and diameter were manually measured with images from a field emission scanning electron microscope (FESEM). A sequence of fields was selected at random locations, and an image of each field was acquired. The length and width of approximately 500 fibers for each sample were measured with ImageJ software. Two significantly different length groups (short and long) of amosite were collected (p <0.05). Approximately 95% of separated amosite (n = 499) using the filtration system were shorter than 5 µm (short fiber group), and approximately 80% of separated amosite (n = 503) using the shaking system were longer than 5 µm (long fiber group).

A Bayesian Approach for Determining the Relationship Between Various Elongate Mineral Particles (EMPs) Definitions.

A variety of dimensions (lengths and widths) of elongate mineral particles (EMPs) have been proposed as being related to health effects. In this paper, we develop a mathematical approach for deriving numerical conversion factors (CFs) between these EMP exposure metrics and applied it to the Minnesota Taconite Health Worker study which contains 196 different job exposure groups (28 similar exposure groups times 7 taconite mines). This approach comprises four steps: for each group (i) obtain EMP dimension information using ISO-TEM 10312/13794 analysis; (ii) use bivariate lognormal distribution to characterize overall EMP size distribution; (iii) use a Bayesian approach to facilitate the formation of the bivariate lognormal distribution; (iv) derive conversion factors between any pair of EMP definitions. The final CFs allow the creation of job exposure matrices (JEMs) for alternative EMP metrics using existing EMP exposures already characterized according to the National Institute of Occupational Safety and Health (NIOSH)-defined EMP exposure metric (length >5 µm with an aspect ratio ≥3.0). The relationships between the NIOSH EMP and other EMP definitions provide the basis of classification of workers into JEMs based on alternate definitions of EMP for epidemiological studies of mesothelioma, lung cancer, and non-malignant respiratory disease.