Inhalation Toxicology

About the journal

Publisher: Informa Healthcare
Published: 1989 to the present, England
Language: English
ISSN: 0895-8378 (print), 1091-7691 (electronic)
Its record in the NLM Catalog

2020s

Elongated particulate burden in an individual who died of mesothelioma and had an occupational history as a talc "mucker". R.F. Dodson, J. Moline, C.D. Salinas, et al. 2024;36(3):205-216. Case report PubMed · Publisher

Abstract

Introduction: Tissue from a 77-year-old man diagnosed with mesothelioma was referred with a request for identification of the presence of fibrous structures in tissue samples. The individual's work history including working as a "mucker" at a specific "industrial" talc mine.

Methods: Ferruginous bodies in the tissue digests as well as asbestos fibers were found. A bulk sample of a talc containing product from that mine was also analyzed.

Discussions/Conclusions: The correlation between the unique asbestos mineral/fibrous content of the talc to which he was exposed and findings of the same type of asbestos found in his lung is discussed. The type of asbestos found (tremolite) is a "non-commercial" type of asbestos that has been identified in some talc deposits. Tremolite, like all forms of asbestos is a causative agent for mesothelioma-the disease from which this individual suffered.
Evaluation of airborne asbestos concentrations associated with the maintenance of brakes on an industrial overhead crane. T. Ferracini, S. Brown, B. Simmons, et al. 2024;36(6):391-405. PubMed · Publisher

Abstract

Objectives: To evaluate potential airborne asbestos exposures during brake maintenance and repair activities on a P&H overhead crane, and during subsequent handling of the mechanic's clothing.

Methods: Personal (n = 27) and area (n = 61) airborne fiber concentrations were measured during brake tests, removal, hand sanding, compressed air use, removal and reattachment of chrysotile-containing brake linings, and reinstallation of the brake linings. The mechanic's clothing was used to measure potential exposure during clothes handling.

Results: All brake linings contained between 19.9% to 52.4% chrysotile asbestos. No amphibole fibers were detected in any bulk or airborne samples. The average full-shift airborne chrysotile concentration was 0.035 f/cc (PCM-equivalent asbestos-specific fibers, or PCME). Average task-based personal air samples collected during brake maintenance, sanding, compressed air use, and brake lining removal tasks ranged from 0 to 0.48 f/cc (PCME). The calculated 30-minute time-weighted average (TWA) airborne chrysotile concentration associated with 5-15 minutes of clothes handling was 0-0.035 f/cc PCME.

Conclusion: The results indicated that personal and area TWA fiber concentrations measured during all crane brake maintenance and clothes handling tasks were below the current OSHA 8-h TWA Permissible Exposure Limit for asbestos of 0.1 f/cc. Further, no airborne asbestos fibers were measured during routine brake maintenance tasks following the manufacturer's maintenance manual procedures. All short-term airborne chrysotile concentrations measured during non-routine tasks were below the current 30-minute OSHA excursion limit for asbestos of 1 f/cc. This study adds to the available data regarding chrysotile exposure potential during maintenance on overhead cranes.
The presence of erionite in North American geologies and the estimated mesothelioma potency by region. M.E. Stevens, D.J. Paustenbach, N.J. Lockhart, et al. 2024;36(3):158-173. PubMed · Publisher

Abstract

Objective: Erionite is a naturally occurring fibrous mineral found in soils in some geographical regions. Known for its potency for causing mesothelioma in the Cappadocia region of Turkey, the erionite fiber has attracted interest in the United States due to its presence in a band of rock that extends from Mexico to Montana. There are few toxicology studies of erionite, but all show it to have unusually high chronic toxicity. Despite its high potency compared to asbestos fibers, erionite has no occupational or environmental exposure limits. This paper takes what has been learned about the chemical and physical characteristics of the various forms of asbestos (chrysotile, amosite, anthophyllite, and crocidolite) and predicts the potency of North American erionite fibers.

Materials And Methods: Based on the fiber potency model in Korchevskiy et al. (2019) and the available published information on erionite, the estimated mesothelioma potency factors (the proportion of mesothelioma mortality per unit cumulative exposure (f/cc-year)) for erionites in the western United States were determined.

Results And Discussion: The model predicted potency factors ranged from 0.19 to 11.25 (average ∼3.5), depending on the region. For reference, crocidolite (the most potent commercial form of asbestos) is assigned a potency factor ∼0.5.

Conclusion: The model predicted mesothelioma potency of Turkish erionite (4.53) falls in this same range of potencies as erionite found in North America. Although it can vary by region, a reasonable ratio of average mesothelioma potency based on this model is 3,000:500:100:1 comparing North American erionite, crocidolite, amosite, and chrysotile (from most potent to least potent).
Lung asbestos fiber burden analysis: effects of the counting rules for legal medicine evaluations. A.B. Somigliana, P.G. Barbieri, A. Cavallo, et al. 2023;35(11-12):300-307. PubMed · Publisher

Abstract

Objectives: The work shows the effect of counting rules, such as analysis magnification and asbestos fiber dimension to be count (with length ≥5 µm or also asbestos fibers with length <5 µm) in the lung asbestos fiber burden analysis for legal medicine evaluations.

Methods: On the same lung tissue samples, two different analyses were carried out to count any asbestos fibers with length ≥1 µm and with length ≥5 µm. Results of the amphibole burden of the two analyses were compared by linear regression analysis on log10-transformed values.

Results: The analysis should be carried out at an appropriate magnification and on samples prepared in such a way as they allow the counting of very fine fibers. If the analysis is limited to the asbestos fibers with length ≥5 µm, there is a high risk of not detecting possible residual chrysotile fiber burden and thinner crocidolite asbestos fibers.

Conclusions: On average we estimated that 1 amphibole fiber with length ≥5 µm corresponds to ∼8 amphibole fibers with length ≥1 µm in the lung. The values of the Helsinki criteria should be updated taking this into account.
Natural mineral fibers: conducting inhalation toxicology studies - part A: Libby Amphibole aerosol generation and characterization method development. A. Wang, A. Gupta, M.D. Grimm, et al. 2023;35(7-8):201-213. PubMed · Publisher · Free full text

Abstract

Background: Asbestos has been classified as a human carcinogen, and exposure may increase the risk of diseases associated with impaired respiratory function. As the range of health effects and airborne concentrations that result in health effects across asbestos-related natural mineral fiber types are not fully understood, the National Institute of Environmental Health Sciences has established a series of research studies to characterize hazards of natural mineral fibers after inhalation exposure. This paper presents the method development work of this research project.

Results: A prototype nose-only exposure system was fabricated to explore the feasibility of generating natural mineral fiber aerosol for in vivo inhalation toxicity studies. The prototype system consisted of a slide bar aerosol generator, a distribution/delivery system and an exposure carousel. Characterization tests conducted using Libby Amphibole 2007 (LA 2007) demonstrated the prototype system delivered stable and controllable aerosol concentration to the exposure carousel. Transmission electron microscopy (TEM) analysis of aerosol samples collected at the exposure port showed the average fiber length and width were comparable to the bulk LA 2007. TEM coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis further confirmed fibers from the aerosol samples were consistent with the bulk LA 2007 chemically and physically.

Conclusions: Characterization of the prototype system demonstrated feasibility of generating LA 2007 fiber aerosols appropriate for in vivo inhalation toxicity studies. The methods developed in this study are suitable to apply to a multiple-carousel exposure system for a rat inhalation toxicity testing using LA 2007.
Natural mineral fibers: conducting inhalation toxicology studies-part B: development of a nose-only exposure system for repeat-exposure in vivo study of Libby amphibole aerosol. A. Wang, A. Gupta, M.D. Grimm, et al. 2023;35(7-8):214-229. PubMed · Publisher · Free full text

Abstract

Background: Exposure to asbestos is associated with malignant and nonmalignant respiratory disease. To strengthen the scientific basis for risk assessment on fibers, the National Institute of Environmental Health Sciences (NIEHS) has initiated a series of studies to address fundamental questions on the toxicology of naturally occurring asbestos and related mineral fibers after inhalation exposure. A prototype nose-only exposure system was previously developed and validated. The prototype system was expanded to a large-scale exposure system in this study for conducting subsequent in vivo rodent inhalation studies of Libby amphibole (LA) 2007, selected as a model fiber.

Results: The exposure system consisting of six exposure carousels was able to independently deliver stable LA 2007 aerosol to individual carousels at target concentrations of 0 (control group), 0.1, 0.3, 1, 3, or 10 mg/m3. A single aerosol generator was used to provide aerosol to all carousels to ensure that exposure atmospheres were chemically and physically similar, with aerosol concentration as the only major variable among the carousels. Transmission electron microscopy (TEM) coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis of aerosol samples collected at the exposure ports indicated the fiber dimensions, chemical composition, and mineralogy were equivalent across exposure carousels and were comparable to the bulk LA 2007 material.

Conclusion: The exposure system developed is ready for use in conducting nose-only inhalation toxicity studies of LA 2007 in rats. The exposure system is anticipated to have applicability for the inhalation toxicity evaluation of other natural mineral fibers of concern.
Toxicological and epidemiological approaches to carcinogenic potency modeling for mixed mineral fiber exposure: the case of fibrous balangeroite and chrysotile. A.A. Korchevskiy, A.G. Wylie. 2023;35(7-8):185-200. Review PubMed · Publisher

Abstract

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. A.A. Korchevskiy, A.G. Wylie. 2022;34(1-2):24-38. PubMed · Publisher

Abstract

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.
Evaluation of asbestos exposure resulting from simulated application of spiked talcum powders. E.W. Miller, B. Roberts, K. Keeton, et al. 2022;34(13-14):380-398. PubMed · Publisher

Abstract

This study characterizes airborne asbestos exposures resulting from the adult application of cosmetic talc body powders spiked with known concentrations of tremolite. Raw talc ores were spiked with 0.005% and 0.1% asbestiform or non-asbestiform tremolite. Personal samples were collected during 16 simulated events, including puff and shaker application and associated clean-up activities. Airborne fiber levels (PCM) were not significantly different for simulations involving talc spiked with asbestiform and non-asbestiform tremolite (p = 0.6104). For application and clean-up of talc spiked with 0.005% asbestiform tremolite, 2 of 24 (8.3%) samples were above the LOD for TEM (0.003 f/cc). For application of talc spiked with 0.1% asbestiform tremolite, 21 of 24 (87.5%) were above the LOD for TEM. The corresponding mean PCME asbestos concentrations were 0.016 f/cc for puff and shaker for samples collected in the first 15 min, 0.002 f/cc for puff and 0.004 f/cc for shaker in the second 15 min, and 0.005 f/cc for puff and 0.013 f/cc for shaker for the full 30 min. Mean PCME concentrations for samples collected during clean-up following application of talc spiked with 0.1% asbestiform tremolite were 0.003 f/cc for samples collected in the first 15 min following puff application, 0.005 f/cc for samples collected in the second 15 min following shaker application, and 0 f/cc for the remaining clean-up samples. Using the EPA's exposure factors, we determined the range of cumulative asbestiform fiber exposures that would result from product use, assuming asbestiform tremolite was present at 0.1%.
Updated Italian cohort data continues to confirm lack of mesothelioma risk in pooled cohort of international cosmetic talc miners and millers. A.M. Ierardi, E.A. Best, G.M. Marsh. 2022;34(5-6):135-144. PubMed · Publisher

Abstract

Objectives: To assess potential mesothelioma risk following inhalation of cosmetic talc, we updated previous iterations of a pooled cohort analysis, post-study statistical power analysis, and confidence interval function analysis for a pooled cohort of international cosmetic talc miners/millers given new Italian cohort data.

Methods: Five cohorts of cosmetic talc miners/millers were pooled. Expected numbers of mesotheliomas for each cohort were reported by the original authors. We based our post-study statistical power analysis on an a priori one-sided significance level of 0.05, and exact Poisson and approximate distribution probabilities. To evaluate the confidence interval function for the observed pooled mesothelioma standardized mortality ratios (SMRs), we calculated the probability for the upper 100(1-2α)% confidence limit that equals various SMRs of interest.

Results: The pooled cohorts generated a total observation time of 135,524.38 person-years. Overall, 4.14 mesotheliomas were expected (mid-value estimate), though only one case of mesothelioma has been confirmed in the pooled cohort to date. We calculated 71% and 87% post-study power to detect a 2.5-fold or greater and a 3.0-fold or greater increase in mesothelioma, respectively. Our complimentary confidence interval function analysis demonstrated that the probability that the true mesothelioma SMR for the pooled cohort was at or above 2.0 or at or above 3.0 was 0.00235 and 0.00005, respectively.

Conclusions: Based on the updated results of our various analyses, the current epidemiological evidence from cosmetic talc miner/miller cohort studies continues to not support the hypothesis that the inhalation of cosmetic talc is associated with an increased risk of mesothelioma.
Dimensional determinants for the carcinogenic potency of elongate amphibole particles. A.A. Korchevskiy, A.G. Wylie. 2021;33(6-8):244-259. PubMed · Publisher

Abstract

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).
Discrepancies of asbestos body and fiber content between formalin-fixed and corresponding paraffin embedded lung tissue. B.K. Kuhn, F. Barresi, H. Dressel, et al. 2021;33(1):18-24. PubMed · Publisher

Abstract

Background: Formalin-fixed lung tissue and paraffin blocks containing peripheral lung tissue obtained from subjects with an occupational asbestos exposure are both regarded to be suitable to determine asbestos load. Because sample preparation of paraffin blocks requires a more intense treatment than formalin-fixed tissue, we tested whether asbestos analysis of formalin-fixed lung tissue and paraffin blocks obtained from the same patients deliver comparable results.

Materials And Methods: We determined numbers of asbestos bodies (AB) and amphibole asbestos fibers (AF) in formalin-fixed lung tissue and corresponding paraffin blocks from 36 patients. For AB counts, samples were digested in sodium hypochlorite. For AF analysis, tissue was freeze-dried and then ashed. Results were reported as numbers of AB and AF per gram dry lung tissue.

Results: Both AB counts as well as AF counts were lower in paraffin blocks than formalin-fixed lung tissue. Compared to formalin-fixed tissue, the limit of detection was higher for paraffin blocks, rendering more results from paraffin blocks not interpretable than from formalin-fixed tissue (8 samples versus 1 for AB and 15 samples versus 4 for AF).

Discussion And Conclusion: Asbestos analysis of paraffin blocks may lead to underestimation of asbestos exposure. This should be considered when assessing occupational asbestos exposure through lung dust analysis in medico-legal evaluation.
US EPA's TSCA risk assessment approach: a case study of asbestos in automotive brakes. D.G. Dodge, A.M. Engel, R.L. Prueitt, et al. 2021;33(9-14):295-307. PubMed · Publisher

Abstract

The United States Environmental Protection Agency (US EPA) is currently refining its approach for risk assessments conducted under the amended Toxic Substances Control Act (TSCA), largely based on recommendations from the National Academies of Sciences, Engineering, and Medicine (NASEM). We identified several issues with the current TSCA risk assessment approach that were not addressed by NASEM in its recommendations. Here, we demonstrate these issues with a case study of the 'Risk Evaluation for Asbestos, Part 1: Chrysotile Asbestos,' which US EPA released in December 2020. In this evaluation, US EPA found that occupational and some consumer uses of automotive brakes and clutches that contain asbestos result in unreasonable risks. These risks were calculated from estimated exposures during brake work and an inhalation unit risk (IUR) developed for chrysotile asbestos. We found that US EPA overestimated risk as a result of unrealistic inputs to both the exposure and toxicity components of the risk equation, and because the Agency did not fully consider relevant epidemiology and toxicity evidence in its systematic review. Our evaluation demonstrates areas in which the TSCA risk assessment approach could be improved to result in risk evaluations that are supported by the available scientific evidence.
Absence of mesothelioma risk maintained in an expanded international cohort of cosmetic talc miners and millers. A.M. Ierardi, G.M. Marsh. 2020;32(6):257-264. PubMed · Publisher

Abstract

Objectives: Based on novel information for the Vermont cosmetic talc miner/miller cohort, including a reported case of mesothelioma, we sought to update our prior pooled statistical power analyses of mesothelioma incidence among European cosmetic talc miners/millers. With the inclusion of the Vermont cohort, we expanded our pooled analysis by 17,170 person-years of observation.Methods: Cosmetic talc miner/miller cohort studies conducted in Italy, Norway, France, Austria, and Vermont were pooled. The expected numbers of mesothelioma cases for each cohort as reported in these studies were used. Our statistical power analysis was based on an a priori one-sided significance level of 0.05 and Poisson distribution probabilities.Results: A total of 130,514 person-years of observation was generated across the five cohorts. One case of mesothelioma was observed (in the Vermont cohort), while approximately 3.34 cases (a mid-value estimate) were expected overall. Thus, we found that the pooled cohorts had 59% and 78% power to detect a 2.5-fold or greater and a 3.0-fold or greater increase in mesothelioma, respectively. The work history characteristics of the one mesothelioma case, which included mention of prior asbestos exposure on the case's death certificate, do not support a causal link with cosmetic talc exposure.Conclusions: Despite the recent finding of one case of mesothelioma in the Vermont cohort (a case unlikely related to talc exposure), we continue to conclude that the epidemiological evidence from the cosmetic talc miner/miller cohort studies does not support the hypothesis that cosmetic talc exposures are associated with an increased risk of pleural mesothelioma.
Estimates of carbon nanotube deposition in the lung: improving quality and robustness. M.D. Wright, A.J. Buckley, R. Smith. 2020;32(7):282-298. Review PubMed · Publisher

Abstract

Carbon nanotube (CNT) in vivo inhalation studies are increasingly providing estimates of the quantity of material deposited in the lung, generally estimated using standard formulae and pulmonary deposition models. These models have typically been developed and validated using data from studies using sphere-like particles. Given the importance of particle morphology to pulmonary deposition, the appropriateness of such an approach was explored to identify any potential limitations. Aerosolized CNT particles typically form 'fiber-like' and/or 'broadly spherical' agglomerates. A review of currently used deposition models indicates that none have been directly validated against results for CNT, however, models for spherical particles have been extensively validated against a wide range of particle sizes and materials and are thus expected to provide reasonable estimates for most 'broadly spherical' CNT particles, although experimental confirmation of this would be of benefit, especially given their low density. The validation of fiber deposition models is significantly less extensive and, in general, focused on larger particles, e.g. asbestos. This raises concerns about the accuracy of deposition estimates for 'fiber-like' CNT particles and recommendations are made for future research to address this. An appreciation of the uncertainties on CNT deposition estimates is important for their interpretation and thus it is recommended that model sensitivity and uncertainty assessments be undertaken. Issues surrounding the measurement and derivation of model input data are also addressed, including instrument responses and particle density assessment options. Recommendations are also made for aerosol characterization to 'future-proof' CNT inhalation studies regarding advances in deposition modeling and toxicological understanding.
Inhalation unit risk (IUR) of asbestos based on available science. A. Korchevskiy, J.O. Rasmuson, E.J. Rasmuson, et al. 2020;32(9-10):372-374. Letter PubMed · Publisher
Occupational exposure to carbon fibers impregnated with epoxy resins and evaluation of their respirability. P. Lovreglio, A. Stufano, D. Mele, et al. 2020;32(2):63-67. PubMed · Publisher

Abstract

Objectives: The study aims to investigate occupational exposure to carbon fibers impregnated with epoxy resins (carbon fiber reinforced [CFR]) in workers at an airplane fuselage section construction plant, by environmental and biological monitoring.Materials and methods: Determination of airborne CFR was done by environmental sampling with active samplers, 11 of which were stationary and 19 personal samplings. The subsequent analyses were performed in the scanning electron microscope fitted with an X-ray microanalysis system (SEM-EDXA). Biological monitoring was carried out by determining CFR in exhaled breath condensate (EBC) collected from 19 male workers who wore personal environmental samplers (exposed workers) and from 10 male workers at the same factory who had no occupational exposure to CFR (internal controls). CFR analysis was done by SEM, applying the method used for determining asbestos fibers in aqueous samples.Results: The airborne CFR concentrations were found to be significantly higher (p = 0.03) at personal samplings (median value 7.01 ff/L, range 1.24-11.16 ff/L) than stationary samplings (median value 1.93 ff/L, range 0.55-10.09 ff/L). The aerodynamic diameters calculated starting from the length and geometric diameter of the sampled CFRs were always higher than 20 µm. CFR was not found in any of the EBC samples collected from the exposed workers and controls.Conclusions: Despite the evidence of occupational exposure to low concentrations of CFR, the absence of such fibers in the EBC in the exposed workers confirms their non-respirability, as expected based on their aerodynamic diameter.

2010s

Assessment of the physicochemical properties of chrysotile-containing brake debris pertaining to toxicity. M.S.P. Boyles, C.A. Poland, J. Raftis, et al. 2019;31(8):325-342. PubMed · Publisher

Abstract

Grinding and drilling of chrysotile asbestos-containing brake pads during the 20th century led to release of chrysotile, resulting in varying levels of workplace exposures of mechanics. Despite exposures, excess risk of mesothelioma remains in doubt. Objectives: The toxicity of particulates is primarily derived through a combination of physicochemical properties and dose and as such this study aimed to determine properties of asbestos-containing brake debris (BD) which may influence pathogenicity and potential of mesothelioma. Materials and Methods: Chrysotile-containing brake pads were ground - to reflect occupational activities, aerosolized, and size-fractionated to isolate respirable fractions. Analysis of morphology, biodurability, surface charge, and interactions with macrophages were undertaken. Results: The respirable fraction of BD contained ∼15-17% free chrysotile fibers thereby constituting a small but relevant potential long fiber dose. Acellular biodurability studies showed rapid dissolution and fragmentation of chrysotile fibers that was consistent for pure chrysotile control and BD samples. Conclusions: The long, free, respirable chrysotile fibers were present in BD, yet were of low bio-durability; incubation in artificial lysosomal fluid led to destruction of free fibers.
Autoimmune markers for progression of Libby amphibole lamellar pleural thickening. J.C. Pfau, T. McNew, K. Hanley, et al. 2019;31(11-12):409-419. PubMed · Publisher · Free full text

Abstract

Exposure to Libby Asbestiform Amphibole (LAA) is associated with asbestos-related diseases, including mesothelioma, pulmonary carcinoma, pleural fibrosis, and systemic autoimmune diseases. The pleural fibrosis can manifest as a rapidly progressing lamellar pleural thickening (LPT), which causes thoracic pain, dyspnea, and worsening pulmonary function tests (PFT). It is refractory to treatment and frequently fatal.Objective: Because of the immune dysfunction that has been described in the LAA-exposed population and the association of pleural manifestations with the presence of autoantibodies, this study tested whether specific immunological factors were associated with progressive LPT and whether they could be used as markers of progressive disease.Methods: Subjects were placed into three study groups defined as (1) progressive LPT, (2) stable LPT, (3) no LPT. Serum samples were tested for antinuclear autoantibodies, mesothelial cell autoantibodies, anti-plasminogen antibodies, IL1 beta, and IL17; which have all been shown to be elevated in mice and/or humans exposed to LAA.Results: Group 1 had significantly higher mean values for all of the autoantibodies, but not IL1 or IL-17, compared to the control Group 3. All three autoantibody tests had high specificity but low sensitivity, but ROC area-under-the-curve values for all three antibodies were over 0.7, statistically higher than a test with no value. When all LPT subjects were combined (Progressive plus Stable), no marker had predictive value for disease.Conclusion: The data support the hypothesis that progressive LPT is associated with immunological findings that may serve as an initial screen for progressive LPT.
Empirical model of mesothelioma potency factors for different mineral fibers based on their chemical composition and dimensionality. A. Korchevskiy, J.O. Rasmuson, E.J. Rasmuson. 2019;31(5):180-191. PubMed · Publisher

Abstract

Context: The potency of various mineral fiber types to produce mesothelioma was previously evaluated for numerous cohorts, but the differences in potencies for distinct fiber types have yet to be explained. Objective: To develop an empirical model that would reconstruct mesothelioma potency factors for various types of fiber based on their chemical composition and dimensionality. Methods: Typical chemical composition and dimensionality metrics (aspect ratios) were obtained and combined with mesothelioma potency factors estimated by Hodgson and Darnton method for Quebec chrysotile, South Africa amosite, South Africa and Australian crocidolite, Russian anthophyllite, Libby amphiboles, and Turkey erionite. The forward stepwise log-log regression method was utilized to determine the best combination of input parameters. Results: Mesothelioma potency factors (RM) for selected cohorts were effectively reconstructed utilizing the median aspect ratio of fibers and equivalent fractions of SiO2, total Fe oxides or total equivalent Fe3+ as Fe2O3, and MgO. Modeled potency factors increase as the aspect ratio, SiO2, and total Fe oxide (or Fe2O3) content grow, and as the MgO content diminishes. Correlation coefficients up to 0.999, p < 0.01, were achieved. The models also yield reasonable estimates of mesothelioma potencies for other fiber types, including Bolivian crocidolite, Russian chrysotile, fluoro-edenite, and others. Conclusion: In spite of the empirical approach, the proposed models provide a starting point for targeted studies of mesothelioma mechanisms by elucidating significant contributing physicochemical factors. The models have an exploratory and preliminary character but can potentially be useful to introduce quantitative structure-activity relationship approaches for the toxicology of fibrous minerals.
Letter concerning: Occupational exposures to cosmetic talc and risk of mesothelioma: an updated pooled cohort and statistical power analysis with consideration of latency period by Gary M. Marsh et al. (Inhal Toxicol. 2019 Aug 5:1-11. doi:10.1080/08958378.2019.1645768). M.M. Finkelstein. 2019;31(13-14):429-431. Letter · Comment PubMed · Publisher
Occupational exposures to cosmetic talc and risk of mesothelioma: an updated pooled cohort and statistical power analysis with consideration of latency period. G.M. Marsh, A.M. Ierardi, S.M. Benson, et al. 2019;31(6):213-223. PubMed · Publisher

Abstract

Objectives: We previously published a pooled statistical power analysis of mesothelioma incidence in the Italian, Norwegian, Austrian, and French cosmetic talc miner and miller cohorts. Soon thereafter, updates to the Italian and Norwegian cohorts were published, providing an additional 14,322 person-years of observation. In this study, we provide an updated power analysis using the newly available information. Methods: We pooled the current results regarding pleural cancer/mesothelioma mortality or incidence in four cosmetic talc miner and miller cohorts in Italy, Norway, Austria, and France. We used the expected numbers of cases as reported by the authors and the power analysis was based on an a priori one-sided significance level of 0.05 and Poisson distribution probabilities. Results: There was a pooled total of 113,344 person-years in the cohorts. Although 3.0 pleural cancers/mesotheliomas were expected, there were no reported pleural cancer or mesothelioma cases in any cohort. Our pooled analysis was associated with 79 and 62% power to detect a 3.0-fold and 2.5-fold or greater increase in pleural cancer/mesothelioma, respectively. These favorable power characteristics were effectively maintained when restricting the pooled cohort to workers with a latency period of 30 or more years (observation time from first employment). Conclusions: The epidemiological evidence from the cosmetic talc miner/miller cohort studies does not support the hypothesis that exposure to cosmetic talc is associated with the development of pleural cancer/mesothelioma.
Response to letters regarding "Cosmetic talc as a risk factor for pleural mesothelioma: a weight of evidence evaluation of the epidemiology". B.L. Finley, S.M. Benson, G.M. Marsh. 2018;30(1):1-4. Letter · Comment PubMed · Publisher
Review of refractory ceramic fiber (RCF) toxicity, epidemiology and occupational exposure. L.D. Maxim, M.J. Utell. 2018;30(2):49-71. Review PubMed · Publisher

Abstract

This literature review on refractory ceramic fibers (RCF) summarizes relevant information on manufacturing, processing, applications, occupational exposure, toxicology and epidemiology studies. Rodent toxicology studies conducted in the 1980s showed that RCF caused fibrosis, lung cancer and mesothelioma. Interpretation of these studies was difficult for various reasons (e.g. overload in chronic inhalation bioassays), but spurred the development of a comprehensive product stewardship program under EPA and later OSHA oversight. Epidemiology studies (both morbidity and mortality) were undertaken to learn more about possible health effects resulting from occupational exposure. No chronic animal bioassay studies on RCF have been conducted since the 1980s. The results of the ongoing epidemiology studies confirm that occupational exposure to RCF is associated with the development of pleural plaques and minor decrements in lung function, but no interstitial fibrosis or incremental lung cancer. Evidence supporting a finding that urinary tumors are associated with RCF exposure remains, but is weaker. One reported, but unconfirmed, mesothelioma was found in an individual with prior occupational asbestos exposure. An elevated SMR for leukemia was found, but was absent in the highly exposed group and has not been observed in studies of other mineral fibers. The industry will continue the product stewardship program including the mortality study.
A 30-year mortality and respiratory morbidity study of refractory ceramic fiber workers. G. LeMasters, J.E. Lockey, T.J. Hilbert, et al. 2017;29(10):462-470. PubMed · Publisher

Abstract

Aim: Report mortality (n = 1119), cancer incidence (n = 1207) and radiographic (n = 1451) findings from a 30-year investigation of current and former refractory ceramic fiber (RCF) workers.

Methods: Cause of death, health and work histories, radiographs and spirometry were collected. Mortality and cancer incidence were analyzed. Logistic regression analysis investigated the associations of latency and cumulative fiber exposure (CFE) on radiographic changes.

Results: The mortality study showed no increase in standardized mortality rates (SMR) for lung cancer, but urinary cancers were significantly elevated in the higher exposed group (SMR = 3.62, 95% CI: 1.33-7.88) and leukemia in the total cohort (SMR = 2.51, 95% CI: 1.08-4.94). One death attributed to mesothelioma was identified (SMR = 2.86, 95% CI: 0.07-15.93) in a worker reporting some asbestos exposure. The overall rate of pleural changes was 6.1%, attaining 21.4% in the highest CFE category for all subjects (adjusted odds ratio (aOR) = 6.9, 95% CI: 3.6-13.4), and 13.0% for those with no reported asbestos exposure (OR= 9.1, 95% CI: 2.5-33.6). Prevalence for recent hires (≥1985) was similar to the background. Interstitial changes were not elevated. Localized pleural thickening was associated with small decreases in spirometry results.

Conclusion: Increases in leukemia and urinary cancer but not lung cancer mortality were found. One death attributed to mesothelioma was observed in a worker with self-reported asbestos exposure and a work history where occupational asbestos exposure may have occurred, rendering uncertainties in assigning causation. Radiographic analyses indicated RCF exposure alone is associated with increased pleural but not interstitial changes. Reductions in RCF exposure should continue. The mortality study is ongoing.
A clinical assessment and lung tissue burden from an individual who worked as a Libby vermiculite miner. B. Black, R.F. Dodson, J.R. Bruce, et al. 2017;29(9):404-413. Case report PubMed · Publisher

Abstract

During its days of operation (1920s-1990), the world's largest source of vermiculite was extracted from a mine located near Libby, Montana. The material mined at this site was shipped for various commercial applications to numerous sites in the United States. There was a "fibrous" component with toxic potential within the vermiculite deposit that has resulted in "asbestos-like" diseases/deaths being reported in numerous studies involving miners as well as residents of the town of Libby. The present case involves the clinical assessments of an individual who worked at the mine from 1969 to 1990. He had no other known occupational exposures to fibrous materials. He developed a clinical picture that included "asbestos-like" pathological features and eventually an adenocarcinoma. The clinical assessment including radiographic features will be presented. The evaluation will also include the analytical evaluation of the fibrous/ferruginous body composition of the lung tissue. This is to our knowledge the first time such an extensive evaluation has been conducted in a vermiculite miner from Libby, Montana.
Asbestos fiber length and its relation to disease risk. C.A. Barlow, M. Grespin, E.A. Best. 2017;29(12-14):541-554. Review PubMed · Publisher

Abstract

Differences in chemical and crystalline composition, fiber dimension, aerodynamic characteristics and biodurability are among the critical factors that define the toxicological and pathological consequences of asbestos exposure. Specifically, fiber dimension can impact whether the fiber is respired, whether and how deeply it is deposited in the lung, and how efficiently and rapidly it may be cleared. This paper provides a current, comprehensive evaluation of the weight of evidence regarding the relationship between asbestos fiber length and disease potency (for malignant and nonmalignant endpoints). In vitro studies, animal exposure studies and epidemiology data were reviewed. We found that the data reported over the last several decades consistently support the conclusions that exposure to fibers longer than 10 µm and perhaps 20 µm are required to significantly increase the risk of developing asbestos-related disease in humans and that there is very little, if any, risk associated with exposure to fibers shorter than 5 µm. Fiber length as a predictor of potency has been evaluated by several federal agencies in the U.S. and could significantly influence future regulatory decisions for elongated mineral particles (EMPs) and high-aspect ratio nanoparticles (HARNs).
Comment on "pleural plaques and lung function in the Marysville worker cohort: a re-analysis" by Zu et al. (2016). J.E. Lockey, K. Dunning, T.J. Hilbert, et al. 2017;29(2):43-45. Letter · Comment PubMed · Publisher
Cosmetic talc as a risk factor for pleural mesothelioma: a weight of evidence evaluation of the epidemiology. B.L. Finley, S.M. Benson, G.M. Marsh. 2017;29(4):179-185. Systematic review PubMed · Publisher

Abstract

Objective: Due to some historical (and inaccurate) reports that asbestos might be present in some cosmetic talc products, questions are occasionally raised regarding the potential pleural mesothelioma risks associated with cosmetic talc products. Our objective was to determine the incidence of pleural mesothelioma of individuals exposed to cosmetic talc.

Materials And Methods: We conducted a systematic review of the epidemiological literature for cosmetic talc miners and millers and found three occupational cohort studies that evaluated pleural mesothelioma incidence in workers in Italy, Norway, France, and Austria. We conducted a second literature review to evaluate the incidence and mortality of pleural mesothelioma among patients who received talc pleurodesis treatments before 1965 and found retrospective clinical studies including over 300 patients with follow-up ranging from 14 to 40 years.

Results: There were no mesotheliomas reported in any of the cosmetic talc miner and miller cohorts. A pooled analysis of data from the cohort mortality studies indicated that four mesothelioma deaths would have been expected from the 90,022 person-years of observation, and this was associated with 84% and 67% statistical power to observe a 3-fold or 2.5-fold increase in pleural mesothelioma mortality, respectively. None of the patients who received talc pleurodesis treatments developed mesothelioma.

Conclusion: We conclude that there is no epidemiological evidence to support the hypothesis that exposure to cosmetic talc is associated with the development of pleural mesothelioma.
Evaluation of take-home exposure to asbestos from handling asbestos-contaminated worker clothing following the abrasive sawing of cement pipe. A. Abelmann, J.R. Maskrey, J.T. Lotter, et al. 2017;29(12-14):555-566. PubMed · Publisher

Abstract

Although industrial uses of asbestos have declined since the 1970s, in recent years there has been a renewed interest in para-occupational ("take-home") exposure to these fibers. The aim of this study was to quantify the release of asbestos fibers, if any, during the shaking out of crocidolite- and chrysotile-contaminated clothing in a simulated at-home setting. An exposure study was conducted in which personal and area air samples were collected during the handling (i.e. shake-out) of work clothing (shirt and pants) previously worn by an operator who had cut asbestos-containing cement pipe. During eight "loading" events, the operator cut a historically representative asbestos-containing cement pipe (10% crocidolite and 25% chrysotile) using a powered abrasive saw. Subsequently, 30-minute air samples were collected during four "shake-out" events, each of which consisted of the handling of two complete sets of contaminated work clothes. Samples were analyzed in accordance with NIOSH methods 7400 and 7402. The mean phase contrast microscopy equivalent (PCME) airborne concentrations were 0.52 f/cc (SD = 0.34 f/cc) for total asbestos fibers, 0.36 f/cc (SD = 0.26 f/cc) for chrysotile and 0.17 f/cc (SD = 0.096 f/cc) for crocidolite. Based on likely estimates of the frequency of laundering activities, and assuming that the dusty clothing (1) is not blown off in the occupational setting using compressed air and (2) is not shaken out before entering the home, a family member handling the clothing could potentially have a lifetime cumulative exposure to chrysotile and crocidolite of approximately 0.20 f/cc-year and 0.096 f/cc-year, respectively.
Evaluation of the presence of asbestos in cosmetic talcum products. J.S. Pierce, A.S. Riordan, E.W. Miller, et al. 2017;29(10):443-456. PubMed · Publisher

Abstract

Talc has been used for over a century in a variety of cosmetic products. While pure cosmetic talc (free of asbestos) is not considered a risk factor for mesothelioma, it has been recently suggested that inhalation of cosmetic talc containing trace levels of asbestos is a risk factor for mesothelioma. Bulk analyses of cosmetic talcum products were performed in the 1960s and 1970s, however, the analytical methods used at that time were incapable of determining whether asbestos minerals were present in the asbestiform versus non-asbestiform habit. The distinction between these two mineral habits is critical, as non-asbestiform amphibole minerals do not present an asbestos-related cancer risk via inhalation. As such, we evaluated six historical talcum powders using modern-era analytical methods to determine if asbestos is present, and if so, to identify the mineral habit (asbestiform versus non-asbestiform) of the asbestos. Based on their labels, the products were produced by four manufacturers and sold between 1940 and 1977. The products were analyzed in duplicate by two laboratories using standard protocols. Laboratory A analyzed samples using X-ray diffraction (XRD) and polarized light microscopy (PLM), and Laboratory B analyzed samples using PLM and transmission electron microscopy (TEM) with energy dispersive X-ray analysis (EDX) and selected area electron diffraction (SAED). No asbestiform minerals were found in any of the products. Nonetheless, even if some historical cosmetic talcum products contained trace amounts (≤0.1%) of asbestiform minerals, any resulting asbestos exposure would be expected to be exceedingly low, and comparable to exposures from breathing ambient air.
Letter on: "Cosmetic talc as a risk factor for pleural mesothelioma: a weight of evidence evaluation of the epidemiology". D. Mirabelli. 2017;29(8):341. Letter · Comment PubMed · Publisher
Mesothelial cell autoantibodies upregulate transcription factors associated with fibrosis. J. Gilmer, T. Harding, L. Woods, et al. 2017;29(1):10-17. PubMed · Publisher · Free full text

Abstract

Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies (MCAA). These MCAA have been linked with pleural fibrotic disease in the asbestos exposed community of Libby, Montana, and induce collagen deposition by cultured mesothelial cells. However, the exact intracellular mechanism by which these autoantibodies cause an increase in collagen deposition remains unknown. This study sought to gain insight into the transcription factors involved in the collagen production after human mesothelial cells are exposed to MCAA. In this study, transcription factor activation profiles were generated from human mesothelial cells (Met5A) treated with serum from Libby subjects, and were compared to cells treated with serum cleared of IgG, and therefore containing no MCAA. Analysis of those profiles indicated C/EBP-beta and hypoxia inducible factor 1 alpha (HIF-1α) are significantly increased in the nucleus, indicating activation, due to MCAA exposure compared to controls. Inhibition of either of these transcription factors significantly reduced collagen 1 deposition by these cells following exposure to MCAA. These data suggest autoantibodies are directly involved in type I collagen deposition and may elucidate potential therapeutic targets for autoantibody mediated fibrosis.
Re: Brent L. Finley, Stacey M. Benson & Gary M. Marsh (2017): Cosmetic talc as a risk factor for pleural mesothelioma: a weight of evidence evaluation of the epidemiology, Inhalation Toxicology, DOI: 10.1080/08958378.2017.1336187. M.M. Finkelstein. 2017;29(9):387-388. Letter · Comment PubMed · Publisher

Summary

In this letter, the author responded to a pooled analysis by Finley and colleagues of three epidemiologic studies of cosmetic talc miners. That analysis had found no deaths from mesothelioma in about 99,000 person-years of observation and concluded that there was no epidemiological evidence linking cosmetic talc exposure to pleural mesothelioma. The author argued that the national and regional mesothelioma rates used as comparisons were unsuitable. Those rates would be dominated by heavily exposed workers in manufacturing, shipyards and construction, so a relative risk below 1.0 would be expected for talc miners exposed to low levels of asbestos contamination. As a thought experiment, he compared the talc miners with Quebec chrysotile miners and millers, whose average mesothelioma mortality was 25 per 100,000 person-years (McDonald et al. 1997). If talc miners' asbestos exposures were 10% or 1% of the Quebec levels, 2.5 or 0.25 mesothelioma cases would be expected in 99,000 person-years. Using the Poisson distribution, the chance of observing no cases was 8% and 78%, respectively. A 50/50 chance of observing no cases corresponded to exposure of about 3% of the Quebec level. The author concluded that the evidence was too weak to draw conclusions about risk at these low exposures and that a much larger cohort would be required. He disclosed consulting for American attorneys in cosmetic talc litigation.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Spirometry: a predictor of lung cancer among asbestos workers. B. Świątkowska, N. Szeszenia-Dąbrowska. 2017;29(1):18-22. PubMed · Publisher

Abstract

Objective: The significance of lung function as an independent risk factor for lung cancer remains unclear. The objective of the study is to answer the question if spirometry can identify patients at risk for lung cancer among people occupationally exposed to asbestos dust in the past.

Methods: In order to identify a group of individuals with the highest risk of lung cancer incidence based on lung function levels of FEV1% predicted value, we examined 6882 subjects enrolled in the health surveillance program for asbestos related diseases over the years 2000-2014. We found a total of 110 cases confirmed as primary lung cancer.

Results: Using Cox's proportional hazards model after adjustment for age, gender, number of cigarettes, duration of smoking and cumulative asbestos exposure, we estimated that compared with the subjects with FEV1 ≥90% pred, the HR of lung cancer was 1.40 (95%CI: 0.94-2.08) for the subjects with FEV1 less than 90% and 1.95 (HR = 1.86; 95%CI: 1.12-3.08) for those with FEV1 less than 70%. In addition, probability of the occurrence of lung cancer for FEV1 <90% of the predicted value was HR = 2.19 (95%CI: 1.04-4.61) in the subjects whose time since spirometry and cancer diagnosis was three years or less.

Conclusions: The results strongly support the hypothesis that spirometry can identify patients at a risk of lung cancer development. Regular spirometry should be offered to all patients with a history of asbestos exposure, at least once every three years.
"Rinse and trickle": a protocol for TEM preparation and investigation of inorganic fibers from biological material. R. Vigliaturo, S. Capella, C. Rinaudo, et al. 2016;28(8):357-63. PubMed · Publisher

Abstract

The purpose of this work is to define a sample preparation protocol that allows inorganic fibers and particulate matter extracted from different biological samples to be characterized morphologically, crystallographically and chemically by transmission electron microscopy-energy dispersive spectroscopy (TEM-EDS). The method does not damage or create artifacts through chemical attacks of the target material. A fairly rapid specimen preparation is applied with the aim of performing as few steps as possible to transfer the withdrawn inorganic matter onto the TEM grid. The biological sample is previously digested chemically by NaClO. The salt is then removed through a series of centrifugation and rinse cycles in deionized water, thus drastically reducing the digestive power of the NaClO and concentrating the fibers for TEM analysis. The concept of equivalent hydrodynamic diameter is introduced to calculate the settling velocity during the centrifugation cycles. This technique is applicable to lung tissues and can be extended to a wide range of organic materials. The procedure does not appear to cause morphological damage to the fibers or modify their chemistry or degree of crystallinity. The extrapolated data can be used in interdisciplinary studies to understand the pathological effects caused by inorganic materials.
Authors' response to Finkelstein's letter to the editor regarding our recent review of ambient airborne asbestos concentrations (Abelmann et al., 2015). A. Abelmann, M.E. Glynn, J.S. Pierce, et al. 2016;28(13):581-582. Letter · Comment PubMed · Publisher
Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development. T.A. Brown, A. Holian, K.E. Pinkerton, et al. 2016;28(8):349-56. PubMed · Publisher · Free full text

Abstract

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual's lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.
Historical ambient airborne asbestos concentrations in the United States. M.M. Finkelstein. 2016;28(10):429-30. Comment PubMed · Publisher
Historical state of knowledge of the health risks of asbestos posed to seamen on merchant ships. D.G. Dodge, B.D. Beck. 2016;28(14):637-657. Historical article · Review PubMed · Publisher

Abstract

We examined the development of knowledge concerning the risks posed by asbestos to seamen working aboard merchant ships at sea (i.e. commercial, rather than naval vessels). Seamen were potentially exposed to "in-place" asbestos on merchant ships by performing intermittent repair and maintenance tasks. We reviewed studies measuring airborne asbestos onboard merchant ships and health outcomes of merchant seamen, as well as studies, communications, and actions of U.S. organizations with roles in maritime health and safety. Up to the 1970s, most knowledge of the health risks of asbestos was derived from studies of workers in asbestos product manufacturing and asbestos mining and milling industries, and certain end-users of asbestos products (particularly insulators). We found that attention to the potential health risks of asbestos to merchant seamen began in the mid- to late 1970s and early 1980s. Findings of pleural abnormalities in U.S. seamen elicited some concern from governmental and industry/labor organizations, but airborne asbestos concentrations aboard merchant ships were found to be <1 f/cc for most short-term repair and maintenance tasks. Responses to this evolving information served to warn seamen and the merchant shipping industry and led to increased precautions regarding asbestos exposure. Starting in the 1990s, findings of modest increases in lung cancer and/or mesothelioma in some epidemiology studies of seamen led some authors to propose that a causal link between shipboard exposures and asbestos-related diseases existed. Limitations in these studies, however, together with mostly unremarkable measures of airborne asbestos on merchant ships, preclude definitive conclusions in this regard.
Pleural plaques and lung function in the Marysville worker cohort: a re-analysis. K. Zu, G. Tao, J.E. Goodman. 2016;28(11):514-9. PubMed · Publisher

Abstract

Background: In the 2014 Integrated Risk Information System (IRIS) assessment for Libby amphibole asbestos (LAA), US EPA calculated a reference concentration (RfC) based on the prevalence of pleural plaques in a group of vermiculite workers in Marysville, Ohio. This RfC is based on the assumption that pleural plaques are associated with adverse lung function. In this study, we evaluated the association between pleural plaques and lung function in the Marysville worker cohort to determine whether they are associated with adverse effects or, rather, are more likely a biomarker of cumulative exposure to LAA.

Methods: We obtained the dataset on the Marysville worker cohort from University of Cincinnati, which included information on demographics, occupational exposures and results of chest high-resolution computed tomography (HRCT)/computed tomography (CT) scans and pulmonary function tests (PFTs). We used multivariate linear regression to estimate mean differences in several lung function parameters, and logistic regression to evaluate the odds of abnormal ventilatory patterns, among men with different pulmonary findings on HRCT/CT scans.

Results: No statistically significant differences in FEV1, FVC, FEV1/FVC, TLC, RV or DLCO were observed between workers with normal scans and those with pleural plaques but no other abnormalities. In contrast, workers with other abnormal findings had statistically significant lower FEV1, FVC, TLC and DLCO, compared with those with normal scans.

Conclusions: This study does not indicate that pleural plaques have a significant effect on lung function when past asbestos exposure is accounted for.
The biological effect of asbestos exposure is dependent on changes in iron homeostasis. A.J. Ghio, J.M. Soukup, L.A. Dailey, et al. 2016;28(14):698-705. PubMed · Publisher

Abstract

Functional groups on the surface of fibrous silicates can complex iron. We tested the postulate that (1) asbestos complexes and sequesters host cell iron resulting in a disruption of metal homeostasis and (2) this loss of essential metal results in an oxidative stress and biological effect in respiratory epithelial cells. Exposure of BEAS-2B cells to 50 μg/mL chrysotile resulted in diminished concentrations of mitochondrial iron. Preincubation of these cells with 200 μM ferric ammonium citrate (FAC) prevented significant mitochondrial iron loss following the same exposure. The host response to chrysotile included increased expression of the importer divalent metal transporter-1 (DMT1) supporting a functional iron deficiency. Incubation of BEAS-2B cells with both 200 μM FAC and 50 μg/mL chrysotile was associated with a greater cell accumulation of iron relative to either iron or chrysotile alone reflecting increased import to correct metal deficiency immediately following fiber exposure. Cellular oxidant generation was elevated after chrysotile exposure and this signal was diminished by co-incubation with 200 μM FAC. Similarly, exposure of BEAS-2B cells to 50 μg/mL chrysotile was associated with release of the proinflammatory mediators interleukin (IL)-6 and IL-8, and these changes were diminished by co-incubation with 200 μM FAC. We conclude that (1) the biological response following exposure to chrysotile is associated with complexation and sequestration of cell iron and (2) increasing available iron in the cell diminished the effects of asbestos exposure.
Are pleural plaques an appropriate endpoint for risk analyses?. L.D. Maxim, R. Niebo, M.J. Utell. 2015;27(7):321-34. Review PubMed · Publisher

Abstract

This review summarizes the literature on the relation between the development of pleural plaques and non-malignant and malignant disease in cohorts exposed to asbestos and other fibers. The available evidence indicates that, absent any other pleural disease, the presence of pleural plaques does not result in respiratory symptoms or clinically significant impacts on lung function. For certain types of asbestos, the development of pleural plaques is statistically correlated with malignant disease, but the evidence is consistent with the hypothesis that pleural plaques without other pleural disease are a marker of exposure, rather than an independent risk factor. Pleural plaques have also developed in cohorts exposed to other fibers that have not proven to be carcinogenic. Risk analyses should be based on the avoidance of known adverse conditions, rather than pleural plaques per se.
Historical ambient airborne asbestos concentrations in the United States - an analysis of published and unpublished literature (1960s-2000s). A. Abelmann, M.E. Glynn, J.S. Pierce, et al. 2015;27(14):754-66. Historical article · Review PubMed · Publisher

Abstract

Outdoor concentrations of airborne asbestos have been measured throughout the US over time. However, a thorough review and analysis of these data has not been conducted. The purpose of this study is to characterize asbestos concentrations in ambient air by environment type (urban, rural) and by decade, using measurements collected in the absence of known asbestos emission sources. A total of 17 published and unpublished studies and datasets were identified that reported the results of 2058 samples collected from the 1960s through the 2000s across the US. Most studies did not report asbestos fiber type, and data based on different analytical methods (e.g. Phase Contrast Microscopy, Transmission Electron Microscopy, etc.) were combined in the dataset; however, only fibers ≥5 μm in length were considered. For a small subset of the measurements (n = 186, 9.0%), a conversion factor was used to convert mass-based data (e.g. ng/m(3)) to count-based values (i.e. f/cc ≥5 μm). The estimated overall mean and median ambient asbestos concentrations for the 1960s through 2000s were 0.00093 f/cc and 0.00022 f/cc, respectively. Concentrations generally increased from the 1960s through the early 1980s, after which they declined considerably. While asbestos use decreased throughout the 1970s, these results indicate that ambient concentrations peaked during the early 1980s, which suggests the possible contribution of abatement or demolition activities. Lastly, ambient asbestos concentrations were higher in urban than rural settings, which is consistent with the greater use of asbestos-containing materials in more densely populated areas.
Measured removal rates of chrysotile asbestos fibers from air and comparison with theoretical estimates based on gravitational settling and dilution ventilation. J. Sahmel, H.J. Avens, P.K. Scott, et al. 2015;27(14):787-801. PubMed · Publisher

Abstract

Context: Industrial hygiene assessments often focus on activity-based airborne asbestos concentration measurements, but few empirical data exist regarding the fiber removal rate from air after activities cease.

Objective: Grade 7T chrysotile indoor fiber settling (FS) rates were characterized using air sampling (NIOSH Method 7402).

Materials And Methods: Six replicate events were conducted in a 58 m(3) study chamber (ventilation 3.5 ACH), in which chrysotile-contaminated work clothing was manipulated for 15 min followed by 30 min of no activity. The fiber concentration decay constant and removal rate were characterized using an exponential decay model based on the measurements.

Results: Breathing zone airborne chrysotile concentrations decreased by 86% within 15-30 min after fiber disturbance, compared to concentrations during active disturbance (p < 0.05). Estimated mean time required for 99% of the phase contrast microscopy-equivalent (PCME) fibers to be removed from air was approximately 30 min (95% CI: 22-57 min). The observed effective FS velocity was 0.0034 m/s. This settling velocity was between 4.5-fold and 180-fold faster than predicted by two different particulate gravitational settling models. Additionally, PCME concentrations decreased approximately 2.5-fold faster than predicted due to air exchange alone (32 versus 79 min to 99% decrease in concentration).

Discussion: Other measurement studies have reported similar airborne fiber removal rates, supporting the finding that factors other than gravitational settling and dilution ventilation contribute measurably to PCM fiber removal from air (e.g. impaction, agglomeration).

Conclusion: Overall, the scientific weight of evidence indicates that the time necessary for removal of 99% of fibers greater than 5 μm in length (with aspect ratios greater than 3:1) is approximately 20-80 min.
Systematic review of pleural plaques and lung function. L.E. Kerper, H.N. Lynch, K. Zu, et al. 2015;27(1):15-44. Systematic review PubMed · Publisher · Free full text

Abstract

Context: US EPA proposed a Reference Concentration for Libby amphibole asbestos based on the premise that pleural plaques are adverse and cause lung function deficits.

Objective: We conducted a systematic review to evaluate whether there is an association between pleural plaques and lung function and ascertain whether results were dependent on the method used to identify plaques.

Methods: Using the PubMed database, we identified studies that evaluated pleural plaques and lung function. We assessed each study for quality, then integrated evidence and assessed associations based on the Bradford Hill guidelines. We also compared the results of HRCT studies to those of X-ray studies.

Results: We identified 16 HRCT and 36 X-ray studies. We rated six HRCT and 16 X-ray studies as higher quality based on a risk-of-bias analysis. Half of the higher quality studies reported small but statistically significant mean lung function decrements associated with plaques. None of the differences were clinically significant. Many studies had limitations, such as inappropriate controls and/or insufficient adjustment for confounders. There was little consistency in the direction of effect for the most commonly reported measurements. X-ray results were more variable than HRCT results. Pleural plaques were not associated with changes in lung function over time in longitudinal studies.

Conclusion: The weight of evidence indicates that pleural plaques do not impact lung function. Observed associations are most likely due to unidentified abnormalities or other factors.
Cumulative Retrospective Exposure Assessment (REA) as a predictor of amphibole asbestos lung burden: validation procedures and results for industrial hygiene and pathology estimates. J.O. Rasmuson, V.L. Roggli, F.W. Boelter, et al. 2014;26(1):1-13. PubMed · Publisher · Free full text

Abstract

Context: A detailed evaluation of the correlation and linearity of industrial hygiene retrospective exposure assessment (REA) for cumulative asbestos exposure with asbestos lung burden analysis (LBA) has not been previously performed, but both methods are utilized for case-control and cohort studies and other applications such as setting occupational exposure limits.

Objective: (a) To correlate REA with asbestos LBA for a large number of cases from varied industries and exposure scenarios; (b) to evaluate the linearity, precision, and applicability of both industrial hygiene exposure reconstruction and LBA; and (c) to demonstrate validation methods for REA.

Methods: A panel of four experienced industrial hygiene raters independently estimated the cumulative asbestos exposure for 363 cases with limited exposure details in which asbestos LBA had been independently determined. LBA for asbestos bodies was performed by a pathologist by both light microscopy and scanning electron microscopy (SEM) and free asbestos fibers by SEM. Precision, reliability, correlation and linearity were evaluated via intraclass correlation, regression analysis and analysis of covariance. Plaintiff's answers to interrogatories, work history sheets, work summaries or plaintiff's discovery depositions that were obtained in court cases involving asbestos were utilized by the pathologist to provide a summarized brief asbestos exposure and work history for each of the 363 cases.

Results: Linear relationships between REA and LBA were found when adjustment was made for asbestos fiber-type exposure differences. Significant correlation between REA and LBA was found with amphibole asbestos lung burden and mixed fiber-types, but not with chrysotile. The intraclass correlation coefficients (ICC) for the precision of the industrial hygiene rater cumulative asbestos exposure estimates and the precision of repeated laboratory analysis were found to be in the excellent range. The ICC estimates were performed independent of specific asbestos fiber-type.

Conclusions: Both REA and pathology assessment are reliable and complementary predictive methods to characterize asbestos exposures. Correlation analysis between the two methods effectively validates both REA methodology and LBA procedures within the determined precision, particularly for cumulative amphibole asbestos exposures since chrysotile fibers, for the most part, are not retained in the lung for an extended period of time.
Efficacy of screens in removing long fibers from an aerosol stream--sample preparation technique for toxicology studies. B.K. Ku, G.J. Deye, L.A. Turkevich. 2014;26(2):70-83. PubMed · Publisher · Free full text

Abstract

Fiber dimension (especially length) and biopersistence are thought to be important variables in determining the pathogenicity of asbestos and other elongate mineral particles. In order to prepare samples of fibers for toxicology studies, it is necessary to develop and evaluate methods for separating fibers by length in the micrometer size range. In this study, we have filtered an aerosol of fibers through nylon screens to investigate whether such screens can efficiently remove the long fibers (L >20 µm, a typical macrophage size) from the aerosol stream. Such a sample, deficient in long fibers, could then be used as the control in a toxicology study to investigate the role of length. A well-dispersed aerosol of glass fibers (a surrogate for asbestos) was generated by vortex shaking a Japan Fibrous Material Research Association (JFMRA) glass fiber powder. Fibers were collected on a mixed cellulose ester (MCE) filter, imaged with phase contrast microscopy (PCM) and lengths were measured. Length distributions of the fibers that penetrated through various screens (10, 20 and 60 µm mesh sizes) were analyzed; additional study was made of fibers that penetrated through double screen and centrally blocked screen configurations. Single screens were not particularly efficient in removing the long fibers; however, the alternative configurations, especially the centrally blocked screen configuration, yielded samples substantially free of the long fibers.
In vivo genotoxicity evaluation of lung cells from Fischer 344 rats following 28 days of inhalation exposure to MWCNTs, plus 28 days and 90 days post-exposure. J.S. Kim, J.H. Sung, B.G. Choi, et al. 2014;26(4):222-34. PubMed · Publisher

Abstract

Despite their useful physico-chemical properties, carbon nanotubes (CNTs) continue to cause concern over occupational and human health due to their structural similarity to asbestos. Thus, to evaluate the toxic and genotoxic effect of multi-wall carbon nanotubes (MWCNTs) on lung cells in vivo, eight-week-old rats were divided into four groups (each group = 25 animals), a fresh air control (0 mg/m(3)), low (0.17 mg/m(3)), middle (0.49 mg/m(3)), and high (0.96 mg/m(3)) dose group, and exposed to MWCNTs via nose-only inhalation 6 h per day, 5 days per week for 28 days. The count median length and geometric standard deviation for the MWCNTs determined by TEM were 330.18 and 1.72 nm, respectively, and the MWCNT diameters ranged from 10 to 15 nm. Lung cells were isolated from five male and five female rats in each group on day 0, day 28 (only from males) and day 90 following the 28-day exposure. The total number of animals used was 15 male and 10 female rats for each concentration group. To determine the genotoxicity of the MWCNTs, a single cell gel electrophoresis assay (Comet assay) was conducted on the rat lung cells. As a result of the exposure, the olive tail moments were found to be significantly higher (p < 0.05) in the male and female rats from all the exposed groups when compared with the fresh air control. In addition, the high-dose exposed male and middle and high-dose exposed female rats retained DNA damage, even 90 days post-exposure (p < 0.05). To investigate the mode of genotoxicity, the intracellular reactive oxygen species (ROS) levels and inflammatory cytokine levels (TNF-α, TGF- β, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ) were also measured. For the male rats, the H2O2 levels were significantly higher in the middle (0 days post-exposure) and high- (0 days and 28 days post-exposure) dose groups (p < 0.05). Conversely, the female rats showed no changes in the H2O2 levels. The inflammatory cytokine levels in the bronchoalveolar lavage (BAL) fluid did not show any statistically significant difference. Interestingly, the short-length MWCNTs deposited in the lung cells were persistent at 90 days post-exposure. Thus, exposing lung cells to MWCNTs with a short tube length may induce genotoxicity.
Perspectives on refractory ceramic fiber (RCF) carcinogenicity: comparisons with other fibers. H. Greim, M.J. Utell, L.D. Maxim, et al. 2014;26(13):789-810. Review PubMed · Publisher · Free full text

Abstract

In 2011, SCOEL classified RCF as a secondary genotoxic carcinogen and supported a practical threshold. Inflammation was considered the predominant manifestation of RCF toxicity. Intrapleural and intraperitoneal implantation induced mesotheliomas and sarcomas in laboratory animals. Chronic nose-only inhalation bioassays indicated that RCF exposure in rats increased the incidence of lung cancer and similar exposures resulted in mesothelioma in hamsters, but these studies may have been compromised by overload. Epidemiological studies in the US and Europe showed an association between exposure and prevalence of respiratory symptoms and pleural plaques, but no interstitial fibrosis, mesotheliomas, or increased numbers of lung tumors were observed. As the latency of asbestos induced mesotheliomas can be up to 50 years, the relationship between RCF exposure and respiratory malignances has not been fully determined. Nonetheless, it is possible to offer useful perspectives. RCF and rock wool have similar airborne fiber dimensions and biopersistence. Therefore, it is likely that these fibers have similar toxicology. Traditional rock wool has been the subject of numerous cohort and case control studies. For rock wool, IARC (2002) concluded that the epidemiological studies did not provide evidence of carcinogenicity. Based on analogies with rock wool (read across), it is reasonable to believe that increases in lung cancer or any mesotheliomas are unlikely to be found in the RCF-exposed cohort. RCF producers have developed a product stewardship program to measure and control fiber concentrations and to further understand the health status of their workers.
Asbestos-associated mesothelial cell autoantibodies promote collagen deposition in vitro. K.M. Serve, B. Black, J. Szeinuk, et al. 2013;25(14):774-84. PubMed · Publisher · Free full text

Abstract

Fibrosis, characterized by excessive collagen protein deposition, is a progressive disease that can fatally inhibit organ function. Prolonged exposure to pathogens or environmental toxicants such as asbestos can lead to chronic inflammatory responses associated with fibrosis. Significant exposure to amphibole asbestos has been reported in and around Libby, Montana due to local mining of asbestos-contaminated vermiculite. These exposures have been implicated in a unique disease etiology characterized predominantly by pleural disorders, including fibrosis. We recently reported the discovery of mesothelial cell autoantibodies (MCAAs) in the sera of Libby residents and demonstrated a positive and significant correlation with pleural disease; however, a mechanistic link was not determined. Here we demonstrate that MCAAs induce pleural mesothelial cells to produce a collagen matrix but do not affect production of the pro-inflammatory cytokine tumor growth factor-β. While autoantibodies commonly induce a pro-fibrotic state by inducing epithelial-mesenchymal transition (EMT) of target cells, we found no evidence supporting EMT in cells exposed to MCAA positive human sera. Although implicated in other models of pulmonary fibrosis, activity of the protein SPARC (secreted protein, acidic and rich in cysteine) did not affect MCAA-induced collagen deposition. However, matrix formation was dependent on matrix metalloproteinase (MMP) activity, and we noted increased expression of MMP-8 and -9 in supernatants of mesothelial cells incubated with MCAA positive sera compared to control. These data suggest a mechanism by which MCAA binding leads to increased collagen deposition through altering MMP expression and provides an important mechanistic link between MCAAs and asbestos-related, autoimmune-induced pleural fibrosis.
The role of genotoxicity in asbestos-induced mesothelioma: an explanation for the differences in carcinogenic potential among fiber types. C.A. Barlow, L. Lievense, S. Gross, et al. 2013;25(9):553-67. Review PubMed · Publisher

Abstract

The mechanism(s) underlying asbestos toxicity associated with the pathogenesis of mesothelioma has been a challenge to unravel for more than 60 years. A significant amount of research has focused on the characteristics of different fiber types and their potential to induce mesothelioma. These mechanistic studies of fiber toxicity have proceeded along two lines: those demonstrating biochemical mechanisms by which fibers induce disease and those investigating human susceptibility. Most recent studies focused on in vitro genotoxic effects induced by asbestos as the mechanism responsible for asbestos-induced disease. Although asbestos exerts a genotoxic effect at certain concentrations in vitro, a positive response in these tests does not indicate that the chemical is likely to produce an increased risk of carcinogenesis in exposed human populations. Thus far, findings from studies on the effects of fiber type in mesothelial cells are seriously flawed by a lack of a dose response relationship. The common limitation of these in vitro experiments is the lack of attention paid to the complexities of the human anatomy, biochemistry and physiology, which make the observed effects in these experimental systems difficult to extrapolate to persons in the workplace. Mechanistic differences between carcinogenic and genotoxic processes indicate why tests for genotoxicity do not provide much insight regarding the ability to predict carcinogenic potential in workers exposed to asbestos doses in the post-Occupational Safety and Health Administration era. This review discusses the existing literature on asbestos-induced genotoxicity and explains why these studies may or may not likely help characterize the dose-response curve at low dose.
Are airborne refractory ceramic fibers similar to asbestos in their carcinogenicity?. A.M. Walker, L.D. Maxim, M.J. Utell. 2012;24(7):416-24. PubMed · Publisher

Abstract

Background: Animal studies on refractory ceramic fiber (RCF) have led to the suggestion that RCF might resemble asbestos in carcinogenicity. Human data are available to test this hypothesis.

Methods: We compared the occurrence of lung cancer and mesothelioma in 605 men engaged in the manufacture of RCF and followed since 1987 to cancer rates that would have been anticipated if airborne RCF were carcinogenic to the same degree as are crocidolite, amosite or chrysotile asbestos. We integrated the results of workplace exposure monitoring with mortality follow-up using formulas presented by Hodgson and Darnton (2000) to estimate hypothesized risks under different asbestos scenarios.

Results: During 15,281 person-years of observation, there were 12 deaths from lung cancer. General population rates predicted 11.8 cases expected for an observed/expected (O/E) ratio of 1.0. Anticipated numbers of deaths from lung cancer under hypotheses of carcinogenicity similar to that of amphiboles and chrysotile were 62 and 17, allowing for rejection of amphibole-like effects (p < 10(-5)) but not chrysotile-like carcinogenicity (p = 0.15). There were no cases of mesothelioma, as compared to 4.9 anticipated under a crocidolite-like hypothesis (p = 0.007 to reject), 1.0 for amosite (p = 0.38) and 0.05 for chrysotile (p = 0.95).

Conclusion: There was no increase in lung cancer or mesothelioma in these workers exposed to RCF. If the cohort had the same exposure to crocidolite asbestos the number of lung cancer and mesothelioma cases would have been significantly greater than observed. The data do not yet permit a similar conclusion with respect to chrysotile asbestos.
Corrigendum. Are airborne refractory ceramic fibers similar to asbestos in their carcinogenicity?. A.M. Walker, L.D. Maxim, M.J. Utell. 2012;24(13):928-9. PubMed · Publisher

Summary

This corrigendum corrected a 2012 analysis (Inhalation Toxicology 24(7):416–424) that had compared lung cancer and mesothelioma mortality in an ongoing mortality study of workers exposed to refractory ceramic fiber (RCF) with the mortality expected if the cohort had been exposed to asbestos at the same fiber concentrations and for the same time. The original paper had concluded that both would have been significantly greater under crocidolite exposure. After publication, an external reviewer found an error in the lung cancer calculations. Cumulative exposure had not been converted from fiber-months to fiber-years per cubic centimeter. In the corrected table, 12 lung cancer deaths were observed. The expected numbers were 11.8 with no fiber effect, 12.2 if RCF were like chrysotile (p = 0.551), and about 16 if like crocidolite, using the potency value RL = 5 from Hodgson and Darnton (2000). The corrected p value for the crocidolite comparison was 0.196, compared with p < 0.001 originally. The authors therefore stated that observed lung cancer mortality could not be distinguished from that expected under crocidolite exposure. An RL of about 9.2 would have been needed to support the original conclusion. For chrysotile, the corrected values did not change the original conclusion. The mesothelioma calculations contained no error. The cohort's zero mesothelioma deaths remained significantly fewer than expected under crocidolite exposure. The next update of the study was scheduled for 2015. The work was funded by the HTIW Coalition, which represents RCF producers.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Egilman's assessment regarding exposures of auto mechanics to amphiboles is not accurate. D.J. Paustenbach, K.R. White. 2012;24(9):609-13; author reply 614-8. Letter · Comment PubMed · Publisher
Elemental composition of ferruginous bodies and occupational categories: analyses and case studies in Mexico. D. Villeda-Cuevas, D. Quintero-Casas, R.M. Rivera-Rosales, et al. 2012;24(4):201-12. PubMed · Publisher

Abstract

Inorganic fibers form part of the complex mixture of environmental pollutants in Mexico City and in general locations. Upon entering the lungs, some of those fibers are transformed into ferruginous bodies (FB) that can be used as biological markers of exposure to fibers. Hence, the objectives of this study were, first, to describe the most frequent types of FB found in the lungs, and second, to determine the elemental composition of the cores of some of those FB. A total of 264 lung samples collected from autopsies performed at the National Institutes of Health in Mexico City were analyzed. The FB were obtained by digesting the samples in commercial bleach and all the FB were then collected in 0.45 µm Millipore membranes. All the FB obtained from each case were counted directly under bright field microscopy, and then classified by morphology. Results showed from 14.5 FB/g in Category 1 (housewives), to 50.2 FB/g for samples from Category 5 (construction workers), and 152 FB/g for Category 6 (miners). Significant differences were found upon comparing samples from Categories 5/6 to Category 1 (p < 0.05). Type 1 FB were the most frequent ones seen in the samples from Categories 1 to 5. Elemental analyses of the cores of several FB found aluminosilicates, fiberglass, tremolite and amosite asbestos among others. In conclusion, residents of Mexico show exposures to a variety of fibers that induce FB including asbestos.
Functional expression of system x(c)- is upregulated by asbestos but not crystalline silica in murine macrophages. J.C. Pfau, T. Seib, J.J. Overocker, et al. 2012;24(8):476-85. PubMed · Publisher · Free full text

Abstract

Context: Inhalation of asbestos or silica is associated with chronic and progressive diseases, including fibrosis, cancer, and increased risk of systemic autoimmunity. Because there is a need for treatment options for these diseases, a better understanding of their mechanistic etiologies is essential. While oxidative stress in macrophages is an early consequence of these exposures, it may also serve as a signaling mechanism involved in downstream immune dysregulation. The system x(c)(-) exchange protein is induced by oxidative stress, and exchanges equimolor levels of extracellular cystine for intracellular glutamate. Cystine is subsequently reduced to cysteine, the rate-limiting precursor for glutathione synthesis.

Objective: As the primary transporter responsible for cystine/glutamate exchange on macrophages, system x(c)- was hypothesized to be inducible in response to asbestos and silica, and to increase viability through protection from oxidative stress.

Results: When challenged with amphibole asbestos, but not crystalline silica, RAW 264.7 macrophages increased expression of xCT and the rate of cystine/glutamate exchange in sodium-free conditions. This upregulation was prevented with N-acetylcysteine, implicating oxidative stress. Cystine protected the macrophages from asbestos-induced oxidative stress and cell death, supporting the hypothesis that imported cystine was used for synthesis of cellular antioxidants. System x(c)(-) inhibitors, glutamate and S-4-carboxyphenylglycine ((S)-4-CPG), significantly increased oxidative stress and cell death of asbestos-treated macrophages.

Conclusion: System x(c)(-) plays a critical role in survival of macrophages exposed to asbestos, but not silica. These data demonstrate a very early difference in the cellular response to these silicates that may have important downstream implications in the pathologic outcome of exposure.
Letter re Marsh et al. M. Finkelstein. 2012;24(2):139-40; author reply 141-2. Letter · Comment PubMed · Publisher
Report of a recent "brake" through in the fiber burden-mesothelioma dialogue. D. Egilman. 2012;24(2):136-7. Letter · Comment PubMed · Publisher
Transcriptional activation of inflammasome components by Libby amphibole and the role of iron. J.H. Shannahan, A.J. Ghio, M.C. Schladweiler, et al. 2012;24(1):60-9. PubMed · Publisher

Abstract

The induction of the NALP3 inflammasome complex is shown to be necessary for the development of fibrosis after asbestos exposure. Libby amphibole (LA) induces lung inflammation and fibrosis, while complexation of iron (Fe) on fibers inhibits inflammation. In this study we examined the ability of LA to induce the inflammasome cascade and the role of Fe in modulating inflammasome activity. Spontaneously hypertensive rats were exposed intratracheally to either saline (300 μl), deferoxamine (Def) (1 mg), FeCl(3) (21 μg), LA (0.5 mg), Fe-loaded LA (Fe + LA), or LA + Def. Activities of oxidative stress-sensitive enzymes, expression of inflammasome-specific genes, and cytokine proteins in bronchoalveolar lavage fluid were analyzed. Lung enzymes at 4 h and 24 h post-exposure were unchanged. LA increased lung expression of genes including interleukin-1β (IL-1β), cathepsin-B, ASC, NALP3, interleukin (IL)-6 and NFκB. LA+Fe significantly reduced IL-1β and NFκB with a trend of reduction in ASC, NALP3, cathepsin-B and IL-6 expression. Def treatment did not reverse the inhibitory effect of Fe on IL-1β and ASC but reversed IL-6 expression. CCL-7, CCL-12, CXCL-3 and COX-2 were induced by LA while LA+Fe tended to reduce these responses. Phosphorylation of ERK but not MEK was increased at 4 h after LA but not LA+Fe exposure. In conclusion, components of the NALP3 inflammasome are transcriptionally activated acutely during LA-induced inflammation. The key inflammatory regulators IL-1β and NFκB were inhibited in the presence of surface-complexed Fe possibly through decreased ERK signaling upstream of the NALP3 inflammasome. The inflammasome activation by LA may contribute to fibrosis, and Fe may reduce this response and alter compensatory mechanisms in individuals exposed to LA.
Asbestos fiber concentrations in the lungs of brake repair workers: commercial amphiboles levels are predictive of chrysotile levels. G.M. Marsh, A.O. Youk, V.L. Roggli. 2011;23(12):681-8. PubMed · Publisher

Abstract

Objectives: To investigate the impact of extreme data points in Finkelstein's 2009 findings of no association between lung levels of commercial and non-commercial amphiboles (principally tremolite as a marker for chrysotile asbestos) in brake repair workers with mesothelioma.

Methods: We first identified potential outliers, high leverage points, and influential points among lung levels of commercial amphiboles and tremolite among 15 persons whose only known exposure to asbestos was through brake repair work. We used sensitivity analysis and quantile regression to account for extreme data points and model commercial amphibole levels as a predictor of tremolite levels. We also used quantile regression to evaluate whether case-reported duration of employment as a brake repair worker predicted lung levels of commercial amphiboles or tremolite.

Results: We found lung levels of commercial amphiboles are a statistically significant predictor of tremolite levels via sensitivity analysis (r = 0.82, slope estimate P-value = 0.001, R² = 0.68) and quantile regression (slope estimate P-value <0.0001). Our data provide no evidence that duration of employment as a brake repair worker was a predictor of lung levels of tremolite or commercial amphiboles.

Conclusions: Our findings suggest that elevated lung levels of tremolite in the lungs of brake repair workers with elevated levels of amphiboles arose from concurrent exposures to commercial amphibole and chrysotile asbestos in occupational settings other than brake repair work. These findings are supported by five new cases. The weight of the scientific evidence does not support a role for occupational exposure to brake dust and other friction products in the development of mesothelioma.
Government and Navy knowledge regarding health hazards of asbestos: a state of the science evaluation (1900 to 1970). K. Franke, D. Paustenbach. 2011;23 Suppl 3:1-20. Review PubMed · Publisher

Abstract

We evaluated dozens of published and unpublished documents describing the knowledge and awareness of both the scientific community and governmental entities, particularly the US Navy, regarding the health hazards associated with asbestos over time. We divided our analysis into specific blocks of time: 1900-1929, 1930-1959, and 1960-1970. By 1930, it was clear that high occupational exposure to asbestos caused a unique disease (asbestosis). Between about 1938 and 1965, a considerable amount of exposure and epidemiology data were collected by various scientific and government organizations. Between 1960 and 1970, mesothelioma was clearly linked to exposure to amphibole asbestos. Nonetheless, the Navy continued to require the use of asbestos-containing materials on ships, but also recommended that proper precautions be taken when handling asbestos. We concluded that the Navy was arguably one of the most knowledgeable organizations in the world regarding the health hazards of asbestos, and that it attempted to implement procedures that would minimize the opportunity for adverse effects on both servicemen and civilians. Finally, it is apparent from our research that through at least 1970, neither the military nor the private sector believed that the myriad of asbestos-containing products considered "encapsulated" (e.g. gaskets, brakes, Bakelite) posed a health hazard to those working with them.
Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure. D.M. Bernstein, R.A. Rogers, R. Sepulveda, et al. 2011;23(7):372-91. PubMed · Publisher · Free full text

Abstract

The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods. The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos.
The role of cardiovascular disease-associated iron overload in Libby amphibole-induced acute pulmonary injury and inflammation. J. Shannahan, M. Schladweiler, D. Padilla-Carlin, et al. 2011;23(3):129-41. PubMed · Publisher

Abstract

Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-overload and oxidative stress. Healthy male Wistar Kyoto (WKY), spontaneously hypertensive (SH) and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25 or 1.0 mg/rat LA and examined at 1 day, 1 week or 1 month. Although histologically it was not possible to distinguish severity differences between strains in LA-induced initial inflammation and later fibrosis, quantitative assessment of biomarkers showed strain-related differences. LA-induced neutrophilic inflammation was reversible in WKY but persisted more in SH and SHHF. Lung MIP-2 mRNA increased only in WKY at 1 day in response to LA but not in SH and SHHF. Bronchoalveolar lavage fluid (BALF) protein increased in SH but not WKY at 1 week and 1 month, while γ-glutamyltransferase and N-acetyl-β-D-glucosaminidase activities increased in all strains (WKY>SH=SHHF). BALF ferritin levels were high at baseline and increased following LA exposure only in SH and SHHF. Ferritin heavy chain mRNA increased only in SHHF at 1 day. At 1 month ferritin light chain mRNA declined from already high baseline levels in SHHF but increased in WKY and SH suggesting its differential involvement in LA-induced injury in Fe-overload. Unlike WKY, both SHHF and SH failed to increase the lung lining antioxidant, ascorbate, in response to LA. We conclude that underlying CVD-associated Fe-overload is likely linked to persistent lung injury, inflammation and antioxidant decompensation following LA exposure in rats.
The role of iron in Libby amphibole-induced acute lung injury and inflammation. J.H. Shannahan, A.J. Ghio, M.C. Schladweiler, et al. 2011;23(6):313-23. PubMed · Publisher

Abstract

Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99 µm ± 4.53 and width 0.28 µm ± 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl(3), LA bound #17 µg of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 µL), DEF (1 mg), FeCl(3) (21 µg), LA (0.5 mg), FeLA (0.5 mg), or LA + DEF (0.5 mg). LA caused BALF neutrophils to increase 24 h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4 h post-exposure, LA-induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface-complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers.
Exposure assessment of carbon nanotube manufacturing workplaces. J.H. Lee, S.B. Lee, G.N. Bae, et al. 2010;22(5):369-81. PubMed · Publisher

Abstract

Seven CNT (carbon nanotube) handling workplaces were investigated for exposure assessment. Personal sampling, area sampling, and real-time monitoring using an SMPS (scanning mobility particle sizer), dust monitor, and aethalometer were performed to characterize the mass exposure, particle size distribution, and particle number exposure. No workplace was found to exceed the current ACGIH (American Conference of Governmental Industrial Hygienists) TLVs (threshold limit values) and OELs (occupational exposure levels) set by the Korean Ministry of Labor for carbon black (3.5 mg/m(3)), PNOS (particles not otherwise specified; 3 mg/m(3)), and asbestos (0.1 fiber/cc). Nanoparticles and fine particles were most frequently released after opening the CVD (chemical vapor deposition) cover, followed by catalyst preparation. Other work processes that prompted nanoparticle release included spraying, CNT preparation, ultrasonic dispersion, wafer heating, and opening the water bath cover. All these operation processes could be effectively controlled with the implementation of exposure mitigation, such as engineering control, except at one workplace where only natural ventilation was used.
High aspect ratio materials: role of surface chemistry vs. length in the historical "long and short amosite asbestos fibers". M. Tomatis, F. Turci, R. Ceschino, et al. 2010;22(12):984-98. PubMed · Publisher

Abstract

In nanotoxicology the question arises whether high aspect ratio materials should be regarded as potentially pathogenic like asbestos, merely on the base of their biopersistence and length to diameter ratio. A higher pathogenicity of long asbestos fibers is associated to their slower clearance and frustrated phagocytosis. In the past decades, two amosite fibers were prepared and studied to confirm the role of fiber length in asbestos toxicity. Long fiber amosite (LFA) and short fiber amosite (SFA) have here been revisited, to check differences in their surface properties, known to modulate the biological responses elicited. We report: (i) micromorphology (abundance of exposed cylindrical vs. truncated surfaces; (ii) surface reactivity (oxidation and coordination state of surface iron, free radical generation and oxidizing potential); (iii) activation of nitric oxide (NO) synthase in lung epithelial cells, as representative of an inflammatory cell response. LFA shows a higher free radical yield, stimulates, more than SFA, NO production by cells and reacts with ascorbic acid, thus depriving the lung lining layer of its antioxidant defenses. The higher activity of LFA than SFA is ascribed to the presence of Fe2+ ions poorly coordinated to the surface. SFA shows only a large number of loosely bound Fe3+ ions, pristine Fe2+ ions having been oxidized during the grinding process converting LFA into SFA. Several factors determine a higher toxicity of LFA than SFA, beside length. The lesson from asbestos indicates that other features besides aspect ratio contribute to the pathogenic potential of a fiber type. All these aspects should be considered when predicting the possible hazard associated to any new fibrous material proposed to the market, let alone nanofibers.
Inhalation toxicity study of disk-shaped potassium octatitanate particles (terracess TF) in rats following 90 days of aerosol exposure. S. Sakai, K. Inada, A.K. Tanaka, et al. 2010;22(1):56-68. PubMed · Publisher

Abstract

Since fibrous particles such as asbestos and some man-made fibers (MMF) have been known to produce carcinogenic or fibrogenic effects, disk-shaped potassium octatitanate (POT) particles (trade name: Terracess TF) were manufactured as nonfibrous particles. A 90-day inhalation toxicity study of Terracess TF was performed to evaluate comparative inhalation toxicity of the disk shape with a fibrous shape that was previously evaluated. Four groups of 20 male and 15 female rats each were exposed to Terracess TF aerosols at concentrations of 0, 2, 10, or 50 mg/m(3) for 90 days. Ten male and 10 female rats per group were sacrificed at 90 days of exposure. After 90 days of exposure, 5 male rats per group were sacrificed at 3 wk of recovery period and 4-5 male rats per group or 5 female rats per group were sacrificed at 15 wk of recovery for lung clearance and histopathology. The mass median aerodynamic equivalent diameter (MMAED) of the aerosols of test materials ranged from 2.5 to 2.9 microm. There were no test-substance-related adverse effects on clinical observations. At the end of the 90-day exposure, a slight increase in lung-to-body weight ratios was observed at 50 mg/m(3) in male but not in female rats. However, lung weights were within normal limits after 3- or 15-wk recovery periods. Microscopically, inhaled Terracess TF particles were mostly phagocytized by free alveolar macrophages (AMs) in the alveolar airspaces and alveolar walls maintained normal structure at 2 and 10 mg/m(3). At 50 mg/m(3), some alveoli were distended and filled with aggregates of particle-laden AMs. The alveolar walls showed slight type II pneumocyte hyperplasia, but neither proliferative inflammation nor alveolar fibrosis was present at 50 mg/m(3). The clearance half-times for Terracess TF were estimated to be in the order of 6 to 9 mo for the 50-mg/m(3) group and 2 to 3 mo for the 10- and 2-mg/m(3) groups. The lung responses and lung clearance rate were comparable to those of "nuisance" type dusts at these concentrations. Based on interpretation that aggregated particle-laden AMs in alveoli was considered to be an early histopathological sign of lung overloading, an effect level was considered to be 50 mg/m(3) and no-observedadverse- effect level (NOAEL) was 10 mg/m(3). This experiment clearly demonstrated that particle morphology was considered to be an important factor to determine inhaled particle toxicity.
Refractory ceramic fiber (RCF) toxicity and epidemiology: a review. M.J. Utell, L.D. Maxim. 2010;22(6):500-21. Review PubMed · Publisher

Abstract

This paper provides a review of the relevant literature on refractory ceramic fibers (RCFs), summarizing relevant data and information on the manufacture, processing, applications, potential occupational exposure, toxicology, epidemiology, risk analysis, and risk management. RCFs are amorphous fibers used for high-temperature insulation applications. RCFs are less durable/biopersistent than amphibole asbestos, but more durable/biopersistent than many other synthetic vitreous fibers (SVFs). Moreover, as produced/used, some RCFs are respirable. Toxicology studies with rodents using various exposure methods have shown that RCFs can cause fibrosis, lung cancer, and mesothelioma. Interpretation of these animal studies is difficult for various reasons (e.g., overload in chronic inhalation bioassays). Epidemiological studies of occupationally exposed cohorts in Europe and the United States have demonstrated measurable effects (e.g., mild respiratory symptoms and pleural plaques) but no disease (i.e., no interstitial fibrosis, no excess lung cancer, and no mesothelioma) to date. The RCF industry, working cooperatively with various government agencies in the United States, has developed a comprehensive product stewardship program (PSP) to identify and control risks associated with occupational exposure. One provision of the PSP is the adoption of a voluntary recommended exposure guideline (REG) of 0.5 fibers/milliliter (f/ml). Selected on the basis of prudence and demonstrated feasibility, compliance with the REG should reduce risks to levels between 0.073/1000 and 1.2/1000, based on extrapolations from chronic animal inhalation studies.
The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short-term inhalation exposure: interim results. D.M. Bernstein, R.A. Rogers, R. Sepulveda, et al. 2010;22(11):937-62. PubMed · Publisher

Abstract

The pathological response and translocation of a commercial chrysotile product similar to that which was used through the mid-1970s in a joint compound intended for sealing the interface between adjacent wall boards was evaluated in comparison to amosite asbestos. This study was unique in that it presents a combined real-world exposure and was the first study to investigate whether there were differences between chrysotile and amosite asbestos fibers in time course, size distribution, and pathological response in the pleural cavity. Rats were exposed by inhalation 6 h/day for 5 days to either sanded joint compound consisting of both chrysotile fibers and sanded joint compound particles (CSP) or amosite asbestos. Subgroups were examined through 1-year postexposure. No pathological response was observed at any time point in the CSP-exposure group. The long chrysotile fibers (L > 20 microm) cleared rapidly (T(1/2) of 4.5 days) and were not observed in the pleural cavity. In contrast, a rapid inflammatory response occurred in the lung following exposure to amosite resulting in Wagner grade 4 interstitial fibrosis within 28 days. Long amosite fibers had a T(1/2) > 1000 days and were observed in the pleural cavity within 7 days postexposure. By 90 days the long amosite fibers were associated with a marked inflammatory response on the parietal pleural. This study provides support that CSP following inhalation would not initiate an inflammatory response in the lung, and that the chrysotile fibers present do not migrate to, or cause an inflammatory response in the pleural cavity, the site of mesothelioma formation.

2000s

Forsterite exposure causes less oxidative DNA damage and lung injury than chrysotile exposure in rats. A. Takata, H. Yamauchi, T. Toya, et al. 2009;21(9):739-46. PubMed · Publisher

Abstract

Chrysotile (CH) is a pathogenic waste building material that can potentially be rendered innocuous via conversion to forsterite (FO) by heating at high temperatures. We compared the ability of FO and CH to cause oxidative DNA damage and lung injury. A single 1-mg intratracheal dose of CH or FO was administered to rats. Significant changes were observed 3 to 7 days after CH injection in alveolar macrophages, neutrophils, eosinophils, lymphocytes, total protein, and lactate dehydrogenase. High concentrations of 8-hydroxy-29-deoxyguanosine (8-OHdG) were also observed in the macrophages, other infiltrating inflammatory cells, granulomas, and in bronchiolar and alveolar epithelial cells. The overexpression of 8-OHdG was limited to airway epithelial and inflammatory cells surrounding the fibrotic foci 540 days after injection, indicating that the inflammatory effects of CH were persistent yet decreased with time. Compared to the CH group, acute lung inflammation observed in the FO group was less apparent and exhibited no progressive fibrosing lesions. The expression of 8-OHdG was transient and weak in the bronchiolar epithelial cells as well as in the inflammatory cells, consistent with low concentrations of 8-OHdG observed in the lungs. These findings confirm that FO causes significantly less inflammation and oxidative DNA damage in the lungs than CH.
Lung fiber burden in the Nottingham gas mask cohort. G. Berry, F. Pooley, A. Gibbs, et al. 2009;21(2):168-72. PubMed · Publisher

Abstract

A cohort of 1,154 employees, mainly women, who had worked 1940-1945 on the manufacture of military gas masks using filter pads containing 20% crocidolite, was traced through 2003, by which time 65 were known to have died from mesothelioma. The last known death with mesothelioma was in 1994, whereas a further 5 cases would have been expected in those with known duration of exposure. Lung tissue samples, from 50 deaths from mesothelioma and 20 other causes, had been analyzed for mineral fiber content. For ten of the mesothelioma cases data on fiber size were collected. Crocidolite fiber concentrations were analyzed in relation to exposure by time and duration. Fiber concentrations overall fell fairly steadily by decade of death, and increased with length of exposure up to 36 months and then fell sharply. The annual rate of elimination estimated by regression was 7.5% corresponding to a half life of 9.2 years. The proportion of fibers longer than 6 mum increased over time implying that the shorter fibers were eliminated more rapidly than the longer ones. The decline in concentrations with time confirms the hypothesis that crocidolite and, by inference, other amphibole fibers are slowly removed from the lung, but since the longer more carcinogenic fibers were cleared more slowly it is unclear to what extent this clearance explains the slowing down of the increase in mesothelioma mortality from about 40 years from the most recent exposure. The exact biostatistical models which most closely conform with the data remain open to question.
A biopersistence study following exposure to chrysotile asbestos alone or in combination with fine particles. D.M. Bernstein, K. Donaldson, U. Decker, et al. 2008;20(11):1009-28. PubMed · Publisher · Free full text

Abstract

In designing a study to evaluate the inhalation biopersistence of a chrysotile asbestos that was used as a component of a joint-compound, a feasibility study was initiated to evaluate the short-term biopersistence of the chrysotile alone and of the chrysotile in combination with the sanded reformulated joint-compound. Two groups of Wistar rats were exposed to either 7RF3 chrysotile (Group 2) or to 7RF3 chrysotile combined with aerosolized sanded joint-compound (Group 3). In addition, a control group was exposed to filtered-air. The chrysotile used in the Ready Mix joint compound is rapidly removed from the lung. The chrysotile alone exposure group had a clearance half-time of fibers L > 20 microm of 2.2 days; in the chrysotile plus sanded exposure group the clearance half-time of fibers L > 20 microm was 2.8 days. However, across all size ranges there was approximately an order of magnitude decrease in the mean number of fibers remaining in the lungs of Group 3 as compared to Group 2 despite similiar aerosol exposures. Histopathological examination showed that the chrysotile exposed lungs had the same appearance as the filtered-air controls. This study uniquely illustrates that additional concurrent exposure to an aerosol of the sanded joint-compound, with large numbers of fine-particles depositing in the lungs, accelerates the recruitment of macrophages, resulting in a tenfold decrease in the number of fibers remaining in the lung. The increased number of macrophages in the chrysotile/sanded joint exposure group was confirmed histologically, with this being the only exposure-related histological finding reported.
A technical comparison of evaluating asbestos concentration by phase-contrast microscopy (PCM), scanning electron microscopy (SEM), and analytical transmission electron microscopy (ATEM) as illustrated from data generated from a case report. R.F. Dodson, S.P. Hammar, L.W. Poye. 2008;20(7):723-32. Case report PubMed · Publisher

Abstract

As reported in the literature, there are more than 30 different standard methods available for the analysis of asbestos in a variety of situations. The methods include those for determining asbestos concentration in air, water, bulk building materials, surface dust, soil, and lung tissue (Millette, 2006; Dodson, 2006). Knowledge of the various methodologies is essential in determining which methodology is appropriate for any given situation. To better understand the use of various techniques in evaluating asbestos, we use an example of an individual who was a machinist in an auto supply/parts business. His work activity during much of his professional career included grinding, arcing, and drilling brake components. Asbestos has been identified as an important component of friction products, particularly brakes, and exposure to asbestos brake dust is of concern, particularly in workers where grinding, arcing, sanding, and drilling of brake components are recognized as releasing appreciable dust. Various methods can be used to evaluate asbestos in tissue and air. The case reported herein was of an individual who died from a pleural mesothelioma. Paraffin-embedded lung tissue was examined by a laboratory using scanning electron microscopy (SEM) and was reported to contain elevated asbestos body concentrations and five fibers, of which two were asbestos (one chrysotile and one tremolite). Tissue from the same paraffin block was analyzed by the laboratory of one of us (RFD) using analytical transmission electron microscopy (ATEM). While one might think the number of asbestos bodies and fibers would be similar using SEM and ATEM, this was not the case. Slightly elevated numbers of ferruginous asbestos bodies were detected in the digestate by light microscopy. Large numbers of uncoated chrysotile fibers were found by ATEM, but not by SEM. The majority of the chrysotile structures were fibrils whose detection required resolution levels attainable only at higher magnification by ATEM. The findings in this case clearly indicate that analysis of lung tissue digestates by ATEM at a higher magnification (15,000x) identifies significant numbers of asbestos fibers that are not identified by SEM at 1000x. These results further indicate that if causation of an asbestos-induced disease such as mesothelioma is based on asbestos concentration of lung tissue, erroneous conclusions can be made by analyzing tissue only by SEM. Thus, the methodologies that are available to analyze asbestos in lung tissue are extensively discussed here with respect to the type of procedure that should be utilized in various situations.
Biopersistence of rock wool in lungs after short-term inhalation in rats. Y. Kudo, Y. Aizawa. 2008;20(2):139-47. PubMed · Publisher

Abstract

To evaluate the safety of rock wool (RW), an asbestos substitute, we examined the biopersistence of RW fibers in rat lungs based on the changes of fiber number and fiber size (length and diameter) by a nose-only inhalation exposure study. Twenty-four male Fischer 344 rats were exposed to RW fibers at a concentration of 30 mg/m(3) continuously for 3 h daily for 5 consecutive days. Six rats each were sacrificed shortly and at 1, 2, and 4 wk after exposure, and their lung tissues were ashed by a low-temperature plasma asher. Then the fiber numbers and fiber sizes in lungs were determined using a phase-contrast microscope and computed image analyzer. During the study period, the arithmetic mean (SD) values of fiber and weight concentrations were 78.5 (35.7) fibers/cm(3), and 29.9 (28.3) mg/m(3), respectively. The fiber number in lungs 4 wk after exposure significantly decreased from the baseline value (shortly after exposure) (p < .05). The half-life of fibers calculated from the approximate curve was 28 days for all fibers and 16 days for fibers with L > 20 microm, and the rate of decrease in fiber number was 46.3% at 4 wk after exposure (shortly-after group = 100%). Likewise, both length and diameter significantly decreased at 4 wk after exposure (p < .05), probably because fibers were phagosytosed and digested by alveolar macrophages, discharged to outside of the body by mucociliary movement, or dissolved by body fluid. It will be necessary in the future to further confirm the safety of RW fibers by assessing the biopersistence of fibers in the lungs and their pathological effects in our ongoing study performed in accordance with the guidelines established in the "Methods for Determination of Hazardous Properties for Human Health of Man Made Mineral Fibers" (EC protocol).
Chronic inhalation of short asbestos: lung fiber burdens and histopathology for monkeys maintained for 11.5 years after exposure. L.E. Stettler, D.D. Sharpnack, E.F. Krieg. 2008;20(1):63-73. PubMed · Publisher

Abstract

In an earlier report, Platek et al. (1985) presented the results of an 18-month inhalation exposure of rats and monkeys to short chrysotile asbestos. The mean chamber exposure level was 1.0 mg/m(3) with an average of 0.79 fibers/ml > 5 microm in length. Gross and histopathological examination of exposed and control rats indicated no treatment-related lesions. Asbestos bodies adjacent to the terminal bronchioles, but no fibrosis, were found in lung biopsy tissue taken from the exposed monkeys at 10 months post-exposure. Fifteen monkeys (9 exposed and 6 controls) from this study were maintained for 11.5 years following exposure. Lung fiber burdens were determined by transmission electron microscopy. The mean lung burden (+/- standard deviation) for 59 samples from exposed monkeys was 63 +/- 30 x 10(6) fibers/g dry lung (range, 18-139 x 10(6)). The geometric mean fiber length was 3.5 microm with 35% of the fibers being > 5 microm in length. These data indicate some chrysotile fibers are durable in vivo for a significant period of time. Lungs were examined grossly and microscopically. No lesions attributable to the inhalation exposure were noted. Asbestos bodies were seen in the lungs of treated monkeys, primarily in the interstitium near bronchioles or small pulmonary blood vessels (which also may have been near to bronchioles just out of the plane of section).
Chrysotile asbestos causes AEC apoptosis via the caspase activation in vitro and in vivo. T. Kido, Y. Morimoto, E. Asonuma, et al. 2008;20(3):339-47. PubMed · Publisher

Abstract

To determine whether alveolar epithelial cell (AEC) apoptosis via caspase activation is involved in asbestos-induced lung injury, we examined apoptosis, caspase-3 and-9 activation using chrysotile asbestos exposure models in vitro and in vivo. Apoptotic cells were assessed in A549 cells with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method after 48 hours exposure of chrysotile asbestos (5 to 100 ug/cm2). Asbestos exposure induced a dose-dependent increase of apoptotic cells, and both pretreatment with Z-LEHD-FMK (caspase-3 inhibitor) or Z-DEMK-FMK (caspase-9 inhibitor) significantly suppressed asbestos-induced apoptosis. Expression of cleaved caspase-3 and-9 increased significantly from 18 to at least 48 hours after asbestos exposure. In vivo study, either 1 or 2 mg of chrysotile asbestos were administered into rat lungs intratracheally, and the lungs were obtained 3 days, 1 and 2 weeks, 1, 3 and 6 months after the administration. Asbestos exposure increased the number of apoptotic cells and the activation of cleaved caspase-3 and -9 most at 3 days in a dose dependent manner, and continued to increase them until at least 6 months after asbestos exposure. Apoptotic cells and cleaved caspase-3 and -9 positive cells were mainly observed in AECs. These findings suggest that AEC apoptosis via caspase-3 and -9 activation is involved in asbestos-induced lung injury.
Comments on Dodson et al., A technical comparison of evaluating asbestos concentration by phase contrast microscopy (PCM), scanning electron microscopy (SEM), and analytical transmission electron microscopy (ATEM) as illustrated from data generated from a case report. V.L. Roggli, T.A. Sporn, K.J. Butnor. 2008;20(12):1113-4; author reply 1115-7. Comment · Letter PubMed · Publisher
Product stewardship in wollastonite production. L.D. Maxim, R. Niebo, S. Larosa, et al. 2008;20(14):1199-214. PubMed · Publisher

Abstract

In July 2002, NYCO Minerals, Inc., discovered a heretofore unknown contaminant in its wollastonite ore. The contaminant was first believed to be tremolite asbestos. Immediate efforts were made to eliminate this material. Additional studies were initiated to fully characterize the contaminant and its distribution in the ore body. Subsequent study by NYCO and their consultants led to the identification of the contaminant as a transition material (TM) intermediate between tremolite and talc. In vitro dissolution rate measurements indicated that the TM dissolved much more rapidly than tremolite asbestos. This article provides background information on wollastonite mineralogy and NYCO's product stewardship program (PSP). At present, NYCO Minerals uses selective mining to control the trace levels of TM in the ore and finished product verified by periodic monitoring of workplace air and finished product.
Re-creation of historical chrysotile-containing joint compounds. G.P. Brorby, P.J. Sheehan, D.W. Berman, et al. 2008;20(11):1043-53. Historical article PubMed · Publisher · Free full text

Abstract

Chrysotile-containing joint compound was commonly used in construction of residential and commercial buildings through the mid 1970s; however, these products have not been manufactured in the United States for more than 30 years. Little is known about actual human exposures to chrysotile fibers that may have resulted from use of chrysotile-containing joint compounds, because few exposure and no health-effects studies have been conducted specifically with these products. Because limited amounts of historical joint compounds are available (and the stability or representativeness of aged products is suspect), it is currently impossible to conduct meaningful studies to better understand the nature and magnitude of potential exposures to chrysotile that may have been associated with historical use of these products. Therefore, to support specific exposure and toxicology research activities, two types of chrysotile-containing joint compounds were produced according to original formulations from the late 1960s. To the extent possible, ingredients were the same as those used originally, with many obtained from the original suppliers. The chrysotile used historically in these products was primarily Grade 7RF9 from the Philip Carey mine. Because this mine is closed, a suitable alternate was identified by comparing the sizes and mineral composition of asbestos structures in a sample of what has been represented to be historical joint compound (all of which were chrysotile) to those in samples of three currently commercially available Grade 7 chrysotile products. The re-created materials generally conformed to original product specifications (e.g. viscosity, workability, crack resistance), indicating that these materials are sufficiently representative of the original products to support research activities.
Select mortality and cancer incidence among residents in various U.S. communities that received asbestos-contaminated vermiculite ore from Libby, Montana. D.K. Horton, F. Bove, V. Kapil. 2008;20(8):767-75. PubMed · Publisher

Abstract

In response to the significantly elevated asbestosis mortality rates found in Libby, Montana, in 2000, this analysis evaluated whether other communities throughout the United States that received asbestos-contaminated vermiculite ore from Libby experienced similar excess rates of asbestos-related diseases. Standardized mortality ratios were calculated using state death certificates, and standardized incidence ratios were calculated using cancer registry records for populations living near facilities that processed or received Libby vermiculite. This analysis focused primarily on diseases that are directly associated with asbestos exposure (e.g., asbestosis; cancer of the peritoneum, retroperitoneum, and pleura, including mesothelioma; and mesothelioma). Lung cancer and cancers of the digestive system, also associated with asbestos exposure, were not included in the analysis because they have additional risk factors for which exposure information was not available. Data from 70 unique sites in 23 states were evaluated. No statistically significant excesses of asbestosis mortality similar to those in Libby were noted; however, 11 sites (plus a state with 6 pooled sites that were counted as 1 site) had excess rates of mesothelioma and cancer of the peritoneum, retroperitoneum, and pleura. Further investigation should be conducted at these sites with excess rates of mesothelioma and cancer of the peritoneum, retroperitoneum, and pleura by participating state health departments to determine whether exposure to Libby vermiculite might have been a contributing factor.
Separation and characterization of respirable amphibole fibers from Libby, Montana. J.S. Webber, D.J. Blake, T.J. Ward, et al. 2008;20(8):733-40. PubMed · Publisher · Free full text

Abstract

The vermiculite mine in Libby, Montana, was in operation for over 70 yr and was contaminated with asbestos-like amphibole fibers. The mining, processing, and shipping of this vermiculite led to significant fiber inhalation exposure throughout the community, and residents of Libby have developed numerous pulmonary diseases such as lung cancer and mesothelioma. The present study describes the separation of Libby 6-mix into respirable and nonrespirable size fractions by means of aqueous elutriation. The elutriator, designed to separate fibers with aerodynamic diameters smaller than 2.5 microm (respirable) from larger fibers, used an upward flow rate of 3.4 x 10(- 4) cm s(-1). The resultant respirable fraction constituted only 13% of the raw Libby 6-mix mass, and less than 2% of the fibers in the elutriated fraction had aerodynamic diameters exceeding 2.5 microm. Surface area of the elutriated fibers was 5.3 m(- 2) g(-1), compared to 0.53 m(-2) g(-1) for the raw fibers. There were no detectable differences in chemical composition between the larger and smaller fibers. Such harvesting of respirable fractions will allow toxicological studies to be conducted within a controlled laboratory setting, utilizing fiber sizes that may more accurately simulate historical exposure of Libby residents' lungs. Importantly, this work describes a method that allows the use of material enriched in more uniform respirable material than raw Libby 6-mix, making comparisons with other known fiber preparations more valid on a mass basis.
Calcitonin gene-related peptide (CGRP) as hazard marker for lung injury induced by dusts. Y. Morimoto, A. Ogami, H. Nagatomo, et al. 2007;19(3):283-9. PubMed · Publisher

Abstract

Calcitonin gene-related peptide (CGRP), which has a function as a growth factor of epithelial cells, is thought to play a role in pulmonary epithelium repair. In order to establish whether or not CGRP is associated with repair in lung damaged by dust, we examined gene expression of CGRP in the lungs of animal models exposed to different dusts. Male Wistar rats were administered 2 mg of crystalline silica, crocidolite, potassium octatitanate whisker (PT-1), and silicon carbide whisker (SiCW) suspended in saline by a single intratracheal instillation and were sacrificed at 3 d, 1 wk, 1 mo, 3 mo, and 6 mo of recovery time. Pathological findings of advanced pulmonary fibrosis were present in the rats exposed to crystalline silica and crocidolite through the experiment, whereas findings of mild or reversible pulmonary fibrosis were present in those exposed to SiCW and PT-1. The expression of CGRP in rat lung was observed by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme immunometric assay (EIA). In RT-PCR, CGRP gene expression was decreased at the interval of 3 d and 1 wk in the case of crystalline silica and crocidolite; on the other hand, it was increased at 3 d and 1 wk in SiCW and at 3 d, 1 wk, and 3 mo in PT-1-exposed rats. CGRP protein level in lungs exposed to PT-1 and SiCW was also higher than that to silica and crocidolite at 3 d of recovery time. These data suggest that CGRP is associated with repair in lung damaged by different dusts, and that CGRP could be used as a sensitive biomarker to indicate the pathogenicity of dusts.
Carcinogenic hazards from inhaled carbon black, titanium dioxide, and talc not containing asbestos or asbestiform fibers: recent evaluations by an IARC Monographs Working Group. R.A. Baan. 2007;19 Suppl 1:213-28. Review PubMed · Publisher

Abstract

In February 2006, an IARC Monographs Working Group reevaluated the carcinogenic hazards to humans of carbon black, titanium dioxide, and talc, which belong to the group of poorly soluble, low-toxicity particles. The review of the relevant literature and the evaluations by the Working Group will be published in Volume 93 of the IARC Monographs series. This article summarizes the Working Group's conclusions. Epidemiological studies among workers in carbon black production and in the rubber industry provided inadequate evidence of carcinogenicity. The overall data from cancer studies in rodents exposed to carbon black provided sufficient evidence of carcinogenicity. The Working Group evaluated carbon black as possibly carcinogenic to humans, Group 2B. Reviewing the epidemiological studies in the titanium dioxide production industry, the Working Group concluded that there is inadequate evidence of carcinogenicity. Overall, the results from rodent cancer studies with titanium dioxide were considered to provide sufficient evidence. Titanium dioxide was evaluated as possibly carcinogenic to humans, Group 2B. Epidemiological studies on talc miners and millers provided inadequate evidence of carcinogenicity of inhaled talc not containing asbestos or asbestiform fibers. The evidence from rodent cancer studies was considered limited. The Working Group evaluated inhaled talc not containing asbestos or asbestiform fibers as not classifiable as to its carcinogenicity to humans, Group 3. The Working Group noted that prolonged exposure to inhaled particles at sufficiently high concentrations in experimental animals may lead to impairment of normal clearance mechanisms in the alveolar region of the lung, resulting in a continued buildup of particles that eventually leads to excessive lung burdens accompanied by chronic alveolar inflammation. The inflammatory response may give rise to increased generation of reactive oxygen species, cell injury, cell proliferation, fibrosis, induction of mutations, and, ultimately, cancer. Since many of these steps also occur in workers in dusty jobs, such as coal miners, data on cancer in animals obtained under conditions of impaired lung clearance were considered relevant to humans. In addition, impaired lung clearance in rodents exposed to ultrafine particles occurs at much lower mass concentrations than with fine particles, which adds to the human relevance.
Change of heme oxygenase-1 expression in lung injury induced by chrysotile asbestos in vivo and in vitro. H. Nagatomo, Y. Morimoto, A. Ogami, et al. 2007;19(4):317-23. PubMed · Publisher

Abstract

Oxidative stress is thought to be the pathogenesis of pulmonary fibrosis induced by asbestos, and heme oxygenase-1 (HO-1) protects lung tissue against oxidative stress. We hypothesized that HO-1 is also associated with oxidative lung injury caused by exposure to chrysotile asbestos. This study was conducted to investigate the HO-1 expression of lungs in lung injury by chrysotile asbestos in vivo and in vitro. Male Wistar rats were administered 1 mg or 2 mg chrysotile suspended in saline by a single intratracheal instillation and were sacrificed at 3 days, 1 wk, 1 mo, 3 mo, and 6 mo of recovery time. The expression of HO-1 was observed by Western blot analysis, reverse-transcription polymerase chain reaction, and immunostaining. Protein levels of HO-1 increased at from 3 days to 6 mo following intratracheal instillation of 1 or 2 mg chrysotile. The mRNA levels of HO-1 increased at 3 mo and 6 mo following intratracheal instillation of 1 or 2 mg chrysotile. HO-1-positive cells were mainly found in the alveolar macrophages during immunostaining. We then examined HO-1 protein expression in human alveolar epithelial cells (A549). A549 cells were incubated with chrysotile at concentrations of 0, 12.5, 25, 50, and 100 microg/ml over 24 h. Increased expression of HO-1 protein was found following exposure to 25 or 50 microg/ml of chrysotile. Increased expression of HO-1 was also found at 6, 12, 24, and 48 h after exposure to 50 microg/ml of chrysotile with a peak at 24 h. These findings suggest that HO-1 is related to lung injury arising from exposure to chrysotile asbestos in vivo and in vitro.
Fiber deposition in the tracheobronchial region: experimental measurements. Y. Zhou, W.C. Su, Y.S. Cheng. 2007;19(13):1071-8. PubMed · Publisher

Abstract

Fiber deposition efficiency in the tracheobronchial region was studied by using two human airway replicas. Carbon fibers with a monodisperse diameter of 3.66 mu were delivered into lung casts at the flow rates of 15, 45, and 60 L/min. Deposition efficiencies in each airway bifurcation were obtained individually. Even though the data shows large variability among the bifurcations within the same generation, there is a general trend for the data obtained in these two replicas. Our results show that fiber deposition for carbon fibers increases with the Stokes number, indicating that inertial impaction is the dominant mechanism. Also, fiber deposition in the tracheobronchial region is lower than that of spherical particles at a given Stokes number, and is similar to the deposition found in the nasal and oral airways as reported previously. This finding implies that it is easier for fibers to penetrate the upper respiratory tract and to reach the lower airways as compared to spherical particles. Our measurements are in general agreement with data obtained with asbestos fiber as reported in another study using a hollow airway replica. Our study appears to give a higher deposition efficiency than the results obtained using idealized single symmetrical bifurcation models. This demonstrates, again, the importance of using a realistic airway model, including larynx, to simulate the airway geometry and flow pattern of the human respiratory tract.
Histopathological changes in rat lung following intratracheal instillation of silicon carbide whiskers and potassium octatitanate whiskers. A. Ogami, Y. Morimoto, T. Myojo, et al. 2007;19(9):753-8. PubMed · Publisher

Abstract

We evaluated the pattern of pulmonary inflammation for the assessment of the biological hazards of two man-made mineral fibers. Rats were exposed by intratracheal instillation to a 2 mg dose of each of two kinds of man-made mineral fibers (PT1, potassium octatitanate whisker; and SiCW, silicon carbide whisker), or three kinds of comparable respirable particles (crystalline silica, crocidolite asbestos, and titanium dioxide, TiO(2)). The lung tissue was evaluated at 3 day, 1 wk, and 1, 3 and 6 mo after exposure. Digital images taken of the lung sections were examined by morphometric point counting method (PCM). PT1 and SiCW showed a similar inflammatory pattern, which contains temporal inflammation such as moderate alveolitis within 1 wk after the exposure, and in later phase aggregation foci of instilled fibers. Differences in repair patterns of these two man-made mineral fibers showed that the toxicity of these two fibers is less toxic than for crocidolite or crystalline silica. Although SiCW showed a higher inflammation score than TiO(2) within 1 mo after instillation, the inflammation scores and fibrotic changes of PT1 and SiCW were not significant as TiO(2) at 3 mo and 6 mo in this study. Careful use should be recommended when these materials are used in the workplace.
Pulmonary effects and biopersistence of deposited silicon carbide whisker after 1-year inhalation in rats. I. Akiyama, A. Ogami, T. Oyabu, et al. 2007;19(2):141-7. PubMed · Publisher

Abstract

Silicon carbide whisker (SiCW) is a durable asbestos substitute. To clarify the biopersistence, the changes of geometrical configurations of deposited whiskers, and potential carcinogenicity and fibrogenicity, 42 Wistar male rats were exposed to SiCW for 6 h/day, 5 days/wk for 1 yr by inhalation. The mass median aerodynamic diameter (geometric standard deviation, GSD), the geometric mean fiber diameter (GSD), and the geometric mean fiber length (GSD) were 2.4 microm (2.4), 0.5 microm (1.5) and 2.8 microm (2.3), respectively. The daily average exposure concentrations were 2.6 +/- 0.4 mg/m3 (98 +/- 19 fibers/ml) and the rats were sacrificed at 6 days and 3, 6, and 12 mo after the exposure. The SiCW amount deposited in each rat lung at 6 days after the exposure, determined by an x-ray diffraction method, was 5.3 +/- 1.4 mg. The biological half-time (BHT) was 16 mo calculated from the deposited SiCW at 6 days and 3, 6, and 12 mo. The BHT was more prolonged than normal physiological clearance. The diameter of SiCW in the lung at each sacrificed time during 12 mo of clearance after the inhalation did not change. However, as for the length of SiCW in the lung, longer SiCW tended to be retained in the lung as the clearance time increased, especially after 6 mo. The histopathological examination revealed bronchoalveolar hyperplasia (BAH) in 2 rats at 1 yr after the exposure and severe fibrotic changes around aggregated SiCW.
A review of scientific literature examining the mining history, geology, mineralogy, and amphibole asbestos health effects of the Rainy Creek igneous complex, Libby, Montana, USA. B.R. Bandli, M.E. Gunter. 2006;18(12):949-62. Historical article · Review PubMed · Publisher

Abstract

This article reviews the past 90 yr of scientific research directed on multiple aspects of the unique geology and environmental health issues surrounding the vermiculite deposit found at Libby, MT. Hydrothermal alteration and extensive weathering of the ultramafic units resulted in the formation of a rich deposit of vermiculite that was mined for 67 yr and used in numerous consumer products in its expanded form. Later intrusions of alkaline units caused hydrothermal alteration of the pyroxenes, resulting in formation of amphiboles. Some of these amphiboles occur in the asbestiform habit and have been associated with pulmonary disease in former miners and mill workers. Identification of these amphibole asbestos minerals has received little attention in the past, but recent work shows that the majority of the amphibole mineral species present may not be any of the amphibole species currently regulated by government agencies. Epidemiological studies on former miners have, nevertheless, shown that the amphibole asbestos from the Rainy Creek igneous complex is harmful; also, a recent study by the Agency for Toxic Substances and Disease Registry shows that residents of Libby who had not been employed in the vermiculite mining or milling operations also appear to have developed asbestos-related pulmonary diseases at a higher rate than the general public elsewhere. Since November 1999, the U.S. Environmental Protection Agency has been involved in the cleanup of asbestos-contaminated sites in and around Libby associated with the mining and processing of vermiculite.
A review of the federal government's health activities in response to asbestos-contaminated ore found in Libby, Montana. K. Horton, V. Kapil, T. Larson, et al. 2006;18(12):925-40. PubMed · Publisher

Abstract

Vermiculite ore is a naturally occurring fibrous mineral widely used in various consumer products, such as attic insulation, lawn and garden products, and fireproofing material. While most vermiculite ore and products do not pose a health hazard, the vermiculite mined from Libby, MT was contaminated with naturally occurring asbestos. The federal Agency for Toxic Substances and Disease Registry (ATSDR) has documented a significant number of asbestos-related deaths among Libby residents. Additionally, as part of the ongoing investigation, ATSDR has learned that this contaminated ore was shipped to hundreds of locations around the United States for processing. While the Libby mine is now closed, studies from ATSDR and elsewhere show that people who worked in the Libby mine or vermiculite processing facilities may have been exposed to hazardous levels of asbestos while the facilities were in operation. People who lived or worked near these sites also may have been exposed to asbestos if they came into contact with contaminated vermiculite. Prolonged exposure to asbestos can cause serious and life-threatening health conditions, including asbestosis, lung cancer, and mesothelioma. In response, ATSDR has initiated 10 different activities to help evaluate the potential health effects among Libby residents and populations throughout the United States who might have been exposed to the asbestos-contaminated ore found in Montana. Some of these activities include conducting environmental exposure evaluations, health statistics reviews, community screenings, and disease-specific surveillance. This article presents the various follow-up activities that have been conducted to date by ATSDR and partnering state health departments.
Animal models of malignant mesothelioma. A.B. Kane. 2006;18(12):1001-4. Review PubMed · Publisher

Abstract

Animal models of diffuse malignant mesothelioma have historically been used to assess carcinogenicity of various fiber types and to study the pathogenesis of this unusual neoplasm. Pleural and peritoneal mesotheliomas have been induced in rodents following exposure to erionite or asbestos fibers, radionuclides, particulate nickel compounds, and chemicals such as 3-methylcholanthrene. The role of SV40 virus as a cofactor with asbestos fibers in the development of diffuse malignant mesotheliomas in humans has been explored in animal models. SV40 virus alone induces mesotheliomas in hamsters. Generation of new transgenic mouse strains with targeted expression of SV40 large T and small t antigens in the mesothelium would be very useful for mechanistic studies. Human malignant mesotheliomas frequently show hypermethylation or deletions at the Cdkn2a/Arf and Cdkn2b gene loci and deletions or mutations at the NF2 gene locus. Heterozygous Nf2 (+/-) mice exposed to crocidolite asbestos fibers exhibited accelerated development of malignant mesotheliomas compared to wild-type littermates. Loss of the wild-type Nf2 allele, leading to biallelic inactivation, was observed in nine mesothelioma cell lines derived from Nf2 (+/-) mice. Similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homozygous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene. As in the human disease, murine mesotheliomas also showed constitutive activation of Akt. This murine model of asbestos carcinogenesis recapitulates the molecular and histopathological features of the human disease and has significant implications for preclinical testing of novel preventive or therapeutic modalities.
Community exposure to asbestos from a vermiculite exfoliation plant in NE Minneapolis. J. Kelly, G.C. Pratt, J. Johnson, et al. 2006;18(12):941-7. PubMed · Publisher

Abstract

Western Mineral Products/W. R. Grace operated a vermiculite plant in a mixed industrial/residential area of northeast Minneapolis from 1936 to 1989. The plant processed vermiculite ore contaminated with amphibole asbestos from a mine in Libby, MT. Air monitoring in the early 1970s found fiber concentrations in excess of 10 fibers per cubic centimeter of air (f/cc), indicating that worker exposure to asbestos was occasionally 100 times the current occupational standard. Residents of the surrounding community also had direct contact with vermiculite processing wastes (containing up to 10% amphibole asbestos) that were made freely available. Children played on waste piles and neighborhood residents hauled the wastes away for home use. In total, 259 contaminated residential properties have been found to date. Reported emission factors and plant process data were used as inputs to model airborne emissions from the plant over several operating scenarios using the U.S. Environmental Protection Agency (EPA) ISC-Prime model. Results estimate short-term air concentrations of asbestos fibers in residential areas nearest the plant may have at times exceeded current occupational standards. Exposure estimates for other pathways were derived primarily from assessments done in Libby by the U.S. EPA. The Northeast Minneapolis Community Vermiculite Investigation (NMCVI) was conducted by the Minnesota Department of Health to identify and characterize the exposures of a cohort of over 6000 people who live or lived in Northeast Minneapolis and may have been exposed to asbestos. This cohort is now being investigated in a respiratory health screening study conducted by the University of Minnesota and the Minnesota Department of Health.
Conference summary. Directions and needs in asbestos research: new insights. J.C. Pfau, M. Pershouse, E.A. Putnam. 2006;18(12):919-23. PubMed · Publisher

Abstract

The Center for Environmental Health Sciences (CEHS) Conference entitled "Directions and Needs in Asbestos Research: New Insights" was held at the University of Montana in Missoula on July 28 and 29, 2005. Researchers, physicians, health care workers, and federal agency representatives from around the country met for a cross-disciplinary exploration of many issues related to asbestos research. Topics included community and psychosocial issues in biomedical research, asbestos exposure assessment, assessment and mechanisms of asbestos-related diseases, and new research directions. This meeting report is a summary of the conference presentations, and of the topics identified for future research directions. This conference was a follow-up to one hosted by the CEHS in June 2002, and continued to take advantage of opportunities to work with a unique population in Libby, MT, where significant asbestos exposures have occurred due to the mining of asbestos-contaminated vermiculite. The goals of this conference were to bring together experts from diverse fields to identify progress made since the last conference and to develop new research avenues that would allow us to address the research needs in emerging asbestos-exposed populations. Participants indicated that these objectives were met, and expressed enthusiasm for follow-up conferences, tentatively planned for the summer of 2007, to maintain the dialog that has been established regarding directions and needs in asbestos research. Selected papers from the conference are presented in this issue of Inhalation Toxicology.
Evidence and reconstruction of airborne asbestos from unconventional environmental samples. J.S. Webber, M. Getman, T.J. Ward. 2006;18(12):969-73. Historical article PubMed · Publisher

Abstract

The understanding of historical ambient asbestos concentrations is critical to exposure mapping and retrospective health impact studies involving asbestos related diseases. Two presentations at the University of Montana Center for Environmental Health Sciences Asbestos Conference (July 28, 2005) introduced novel methods for detecting evidence of past airborne asbestos contamination. In each of these studies, transmission electron microscopy was used to identify and measure asbestos fibers collected in samples from unconventional environmental sources. In the first study, paleolimnology, analytical transmission electron microscopy, particle-separation techniques, and empirical aerosol-sediment modeling were combined to provide the first measurements of airborne asbestos concentrations prior to the 1980s. In an upstate New York study area, airborne concentrations of chrysotile followed its 20th-century usage, with highest concentrations near mid-century (approximately 0.1 fibers/cm3), followed by a decrease in the last quarter century. Airborne concentrations of anthophyllite asbestos (a contaminant from nearby talc mines and mills) increased from <0.004 to 0.022 fibers/cm3 from 1847 to 1995. In the second study, tree bark and core samples were collected from areas near the asbestos-contaminated vermiculite mine in Libby, MT. We originally hypothesized that trees in the areas surrounding the mine could serve as reservoirs for ambient amphibole fibers. Though gravimetric reduction of a tree core sample did not indicate the presence of amphibole fibers, transmission electron microscopy analysis of bark samples yielded substantial amphibole fiber concentrations ranging from 14 to 260 million amphibole fibers/cm2. Based on these preliminary results, we conclude that trees in the Libby valley can serve as reservoirs for amphibole fibers, and that a continued potential for exposure exists for those who harvest contaminated wood.
Exposure matrix development for the Libby cohort. C.W. Noonan. 2006;18(12):963-7. PubMed · Publisher

Abstract

The Libby, MT, cohort includes current and former residents with potential historical exposure to asbestos-contaminated vermiculite. This cohort includes individuals with a broad range of exposure experiences and work histories. While both occupational and nonoccupational exposure pathways were found to be relevant in recent investigations of health effects among this cohort, there has not been a comprehensive approach to characterizing these varied exposure pathways. Any approach toward assessing historical exposures among this population must account for three general categories: (1) occupational exposures, (2) residential exposures, and (3) exposures related to a variety of nonoccupational activities thought to be associated with vermiculite/asbestos exposure in this community. First, a job exposure matrix is commonly used in occupational epidemiology to assess historical worker exposures, allowing for the incorporation of numerous occupational categories and weighting factors applied to specific jobs for different time periods. Second, residential exposures can best be quantified by integrating individuals' residential histories with data on environmental asbestos contamination in the community. Previous soil or sediment sampling as well as air modeling could inform estimates of time- and spatial-dependent exposure concentrations for a residential exposure matrix. Finally, exposure opportunities due to nonoccupational activities could be weighted by factors such as time, geography, environmental sampling, and an assessment of the relative importance for each pathway. These three matrices for occupational, residential, and activity exposure pathways could be combined or used separately to provide a more comprehensive and quantitative, or semiquantitative, assessment of individual exposure in future epidemiological studies of this cohort.
Mechanism of fiber carcinogenesis: from reactive radical species to silencing of the beta igH3 gene. T.K. Hei, A. Xu, S.X. Huang, et al. 2006;18(12):985-90. PubMed · Publisher

Abstract

Although the U.S. Environmental Protection Agency has restricted the industrial use of regulated forms of asbestos in the United States since the early 1970s, environmental exposure to asbestos remains a health concern in the United States and is a significant health issue among developing countries. Exposure to asbestos is associated with chronic pulmonary diseases and cancer of the lung, pleura, and peritoneum. The mechanism of fiber carcinogenesis is far from clear and is likely to be complex, depending on fiber dimensions, surface properties, and physical durability. The induction of reactive oxygen and nitrogen species upon phagocytosis of fibers plays an important role in fiber genotoxicity. The beta igH3, a secreted protein induced by the transforming growth factor-beta and essential for cell adhesion, is downregulated in asbestos-induced tumorigenic human bronchial epithelial cells. Ectopic expression of the beta igH3 gene abrogates the tumorigenic phenotype and suggests that the gene plays a causal role in fiber carcinogenesis. A better understanding of the carcinogenic mechanism of asbestos and other mineral fibers will provide useful information on interventional and preventive measures for asbestos-mediated diseases such as human pleural and peritoneal mesotheliomas.
Mineral-fluid interaction in the lungs: insights from reaction-path modeling. S.A. Wood, A.E. Taunton, C. Normand, et al. 2006;18(12):975-84. PubMed · Publisher

Abstract

Thermodynamic modeling, in conjunction with available kinetic information, has been employed to investigate the fate of chrysotile and tremolite in the human lung. In particular, we focus on mineral-fluid reactions using techniques borrowed from geochemistry, including calculation of saturation indices, activity-ratio phase diagrams, and reaction-path modeling. Saturation index calculations show that fresh lung fluid is undersaturated with respect to both tremolite and chrysotile and these minerals should dissolve, in accordance with conclusions from previous work described in the literature. Modeling of reaction paths in both closed and open systems confirms previous suggestions that chrysotile dissolves faster than tremolite in lung fluid, which offers an explanation for the apparent increase in tremolite/chrysotile ratios in lungs of miners and millers over time. However, examination of activity-ratio phase diagrams and reaction-path model calculations raises the possibility not only that minerals dissolve congruently in lung fluid, but that secondary minerals such as talc or various Ca-Mg carbonates might potentially form in lung fluid as asbestiform minerals dissolve.
Pleural mesothelioma in a woman whose documented past exposure to asbestos was from smoking asbestos-containing filtered cigarettes: the comparative value of analytical transmission electron microscopic analysis of lung and lymph-node tissue. R.F. Dodson, S.P. Hammar. 2006;18(9):679-84. Case report PubMed · Publisher

Abstract

Asbestos has had many commercial applications, including its use as a major component in various types of filters. Between 1952 and 1956, crocidolite asbestos was used as a component of filters for cigarettes, reportedly greatly reducing tars and nicotine from mainstream smoke. This case report quantifies asbestos burden in lung and lymph node tissue in a 67-yr-old woman who succumbed to mesothelioma. Her only historically documented exposure to asbestos was from smoking crocidolite asbestos-containing filtered cigarettes between 1952 and 1956. Tissue digestion analysis by analytical transmission electron microscopy (ATEM) identified crocidolite fibers in lungs and thoracic lymph nodes. Combined ATEM data of lung and lymph node tissue clarified the patient's exposure to asbestos and particularly to crocidolite asbestos and thus to the presence of an entity recognized as the causal agent for mesothelioma.
The carcinogenicity of WHO fibers of silicon carbide: SiC whiskers compared to cleavage fragments of granular SiC. K. Rödelsperger, B. Brückel. 2006;18(9):623-31. PubMed · Publisher

Abstract

A steep dose-response relationship for tumors was reported after application of 0.05 to 25 mg of whiskers of SiC in 1991 in a chronic intraperitoneal injection study in rats. In contrast, doses of 250 and 1000 mg of granular SiC did not cause tumors. The whiskers contained 107,000,000 fibers longer than 5 mum, per milligram while the granular sample was assumed to be free of such fibers. However, it has since been realized that even granular SiC may contain fibrous fragments that fulfill the definition of WHO fibers. It was the objective of our study to reanalyze the quantity of WHO fibers that were administered with the granular SiC. In addition, we examined whether the potency per WHO fiber was different for the SiC fragments and the SiC whiskers. Samples of the original granular and fibrous SiC were suspended in water and filtered. One half of each filter was analyzed by scanning electron microscopy (SEM, magnification x 2500), and transmission electron microscopy (TEM, x 10,000) was also performed for the SiC whiskers. The concentration of WHO fibers was 58,000 fibers/mg for the granular sample compared to 48,000,000 (SEM) and 42,000,000 (TEM) fibers/mg for the whiskers. The aspect ratio of the WHO fibers exceeded 10/1 for only 3.3% of the fragments but in each analysis for 96% of the whiskers. In addition, 0% of the fragments compared to 44% and 30% of the whiskers were more than 10 mum long. In total, 15 and 58 x 106 WHO fibers were injected with the granular SiC even though only 0.8% and 0% tumors were recorded. However, 20.1% and 43.3% tumors would have been expected if the carcinogenic potency were the same for the fragments and for the whiskers. We therefore conclude that carcinogenic potency is a function of the shapes of the WHO fibers and is much lower for SiC fragments than for whiskers. Hence carcinogenicity mainly is restricted to a subgroup of WHO fibers longer than about 10 and thinner than about 1 mum. This conclusion is in line with the optimal exposure index, which recently has been proposed by the U.S. Environmental Protection Agency (EPA) for asbestos.
The role of SV40 in malignant mesothelioma and other human malignancies. M.A. Pershouse, S. Heivly, T. Girtsman. 2006;18(12):995-1000. Review PubMed · Publisher

Abstract

SV40 is a DNA tumor virus thrust upon human populations primarily as a contaminant in various vaccine preparations. Some estimates suggest that millions of people are currently infected with the virus. The virus causes primary brain tumors, bone tumors, lymphomas, and mesotheliomas when injected into some rodent models. It has also been detected in a similar spectrum of human tumors. However, epidemiological studies have failed to conclusively demonstrate a higher incidence of disease in affected populations. To date, over 60 reports from 49 different laboratories have shown SV40 sequences in tissues from human cancer patients. Six studies, however, have failed to detect evidence of virus in similar tissues. Some have suggested that SV40 may act as a cocarcinogen with asbestos to cause mesothelioma formation, or that it may be responsible for the 10-20% of mesotheliomas with no reported history of asbestos exposure. This report briefly covers the historical evidence for SV40 carcinogenesis and then covers experiments now underway to better understand the role of SV40 in human mesotheliomas.
The toxicological response of Brazilian chrysotile asbestos: a multidose subchronic 90-day inhalation toxicology study with 92-day recovery to assess cellular and pathological response. D.M. Bernstein, R. Rogers, P. Smith, et al. 2006;18(5):313-32. PubMed · Publisher

Abstract

Inhalation toxicology studies with chrysotile asbestos have in the past been performed at exceedingly high doses without consideration of fiber number or dimensions. As such, the exposures have exceeded lung overload levels, making quantitative assessment of these studies difficult if not impossible. To assess the cellular and pathological response in the rat lung to a well-characterized aerosol of chrysotile asbestos, a 90-day subchronic inhalation toxicology study was performed using a commercial Brazilian chrysotile (CA 300). The protocol was based on that established by the European Commission for the evaluation of synthetic vitreous fibers. The study was also designed to assess the potential for reversibility of any such changes and to permit association of responses with fiber dose in the lung and the influence of fiber length. Wistar male rats were randomly assigned to an air control group and to 2 CA 300 exposure groups at mean fiber aerosol concentrations of 76 fibers L > 20 microm/cm3 (3413 total fibers/cm3; 536 WHO fibers/cm3) or 207 fibers L > 20 microm/cm3 (8941 total fibers/cm3; 1429 WHO fibers/cm3). The animals were exposed using a flow-past, nose-only exposure system for 5 days/wk, 6 h/day, during 13 consecutive weeks (65 exposures), followed by a subsequent nonexposure period lasting for 92 days. Animals were sacrificed after cessation of exposure and after 50 and 92 days of nonexposure recovery. At each sacrifice, subgroups of rats were assessed for the determination of the lung burden; histopathological examination; cell proliferation response; bronchoalveolar lavage with the determination of inflammatory cells; clinical biochemistry; and for analysis by confocal microscopy. Through 90 days of exposure and 92 days of recovery, chrysotile at a mean exposure of 76 fibers L > 20 microm/cm3 (3413 total fibers/cm3) resulted in no fibrosis (Wagner score 1.8 to 2.6) at any time point. The long chrysotile fibers were observed to break apart into small particles and smaller fibers. In vitro modeling has indicated that these particles are essentially amorphous silica. At an exposure concentration of 207 fibers L > 20 microm/cm3 (8941 total fibers/cm3) slight fibrosis was observed. In comparison with other studies, chrysotile produced less inflammatory response than the biosoluble synthetic vitreous fiber CMS. As predicted by the recent biopersistence studies on chrysotile, this study clearly shows that at that at an exposure concentration 5000 times greater than the U.S. threshold limit value of 0.1 f(WHO)/cm3, chrysotile produces no significant pathological response.
A review of the toxicology and epidemiology of wollastonite. L.D. Maxim, E.E. McConnell. 2005;17(9):451-66. Review PubMed · Publisher

Abstract

Wollastonite is a naturally occurring calcium silicate (CaSiO(3)) that is produced in both powder and fibrous forms. It is a valuable industrial mineral used in plastics, ceramics, metallurgical applications, paint, and friction products. For some applications wollastonite serves as an asbestos replacement. To varying degrees, wollastonite grades contain respirable particles/fibers, some of which have lengths and diameters that might be biologically active if deposited and retained in the lung. In this review we provide background information on wollastonite properties, markets, production and use, regulatory classification, and occupational exposure limits. We also summarize the available studies on the toxicology and epidemiology of wollastonite. We conclude that there is inadequate evidence for the carcinogenicity of wollastonite in animals and, based on strong evidence that wollastonite is not biopersistent, believe that a well-designed animal inhalation bioassay would have a negative result. The epidemiological evidence for wollastonite is limited, but does not suggest that workers are at significant risk of an increased incidence of pulmonary fibrosis, lung cancer, or mesothelioma. Morbidity studies have demonstrated a nonspecific increase in bronchitis and reduced lung function. It is prudent, however, to continue product stewardship efforts by wollastonite producers to control workplace exposures and to monitor scientific developments.
Comparison of Calidria chrysotile asbestos to pure tremolite: final results of the inhalation biopersistence and histopathology examination following short-term exposure. D.M. Bernstein, J. Chevalier, P. Smith. 2005;17(9):427-49. PubMed · Publisher

Abstract

Calidria chrysotile asbestos, which is a serpentine mineral, has been shown to be considerably less biopersistent than the durable amphibole mineral tremolite asbestos, which persists once deposited in the lung. The initial results of this inhalation biopersistence study in rats that demonstrates this difference were reported in Bernstein et al. (2003). This article presents the full results through 1 yr after cessation of the 5-day exposure. This study was based upon the recommendations of the European Commission (EC) Interim Protocol for the Inhalation Biopersistence of synthetic mineral fibers (Bernstein & Riego-Sintes, 1999). In addition, the histopathological response in the lung was evaluated following exposure. In order to quantify the dynamics and rate by which these fibers are removed from the lung, the biopersistence of a sample of commercial-grade chrysotile from the Coalinga mine in New Idria, CA, of the type Calidria RG144 and that of a long-fiber tremolite were studied. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 microm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and the histopathological response. As the long fibers have been shown to have the greatest potential for pathogenicity, the aerosol generation technique was designed to maximize the number of long respirable fibers. The chrysotile samples were specifically chosen to have 200 fibers/cm3 longer than 20 microm in length present in the exposure aerosol. These longer fibers were found to be largely composed of multiple shorter fibrils. The tremolite samples were chosen to have 100 fibers/cm3 longer than 20 microm in length present in the exposure aerosol. Calidria chrysotile has been found to be one of the most rapidly cleared mineral fibers from the lung. The fibers longer than 20 microm in length are cleared with a half-time of 7 h. By 2 days postexposure all long fibers have dissolved/disintegrated into shorter pieces. The fibers between 5 and 20 microm in length were cleared with a half-time of 7 days. This length range represents a transition zone between those fibers that can be fully phagocytosed and cleared as particles and the longer fibers that cannot be fully engulfed by the macrophage. The fibers/objects shorter than 5 microm in length were cleared with a half-time of 64 days, which is faster than that reported for insoluble nuisance dusts such as TiO2. By 12 months postexposure, 99.92% of all the remaining chrysotile was less than 5 microm in length. Following the 5 days of repeated exposure to more than 48,000 chrysotile fibers/cm3 (190 fibers L > 20 microm), histopathological examination revealed no evidence of any inflammatory reaction either after the cessation of the last exposure or at any time during the subsequent 12-mo period. This is in marked contrast to the amphibole tremolite, which was also investigated using the same inhalation biopersistence protocol. The long tremolite fibers, once deposited in the lung, remain over the rat's lifetime with essentially an infinite half-time. Even the shorter fibers, following early clearance, also remain with no dissolution or further removal. At 365 days postexposure, there was a mean lung burden was of 0.5 million fibers L > 20 microm and 7 million fibers 5-20 microm in length with a total mean lung burden of 19.6 million fibers. The tremolite exposed rats, even with exposure to 16 times fewer total fibers than chrysotile, showed a pronounced inflammatory response with the rapid development of granulomas as seen at day 1 postexposure, followed by the development of fibrosis characterized by collagen deposition within these granulomas and by 90 days even mild interstitial fibrosis. With the short exposure, this study was not designed specifically to evaluate pathological response; however, it is quite interesting that even so there was such a marked response with tremolite. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and the amphibole tremolite. As Calidria chrysotile has been certified to have no tremolite fiber, the results of the current study together with the results from toxicological and epidemiological studies indicate that this fiber is not associated with lung disease.
Expression of heme oxygenase-1 in the lungs of rats exposed to crocidolite asbestos. H. Nagatomo, Y. Morimoto, T. Oyabu, et al. 2005;17(6):293-6. PubMed · Publisher

Abstract

Oxidative stress is thought to be the pathogenesis of pulmonary fibrosis induced by asbestos, and heme oxygenase-1 (HO-1) protects lung tissue against oxidative stress. We hypothesized that HO-1 is associated with oxidative lung injury caused by exposure to asbestos. This study was conducted to investigate the time course of HO-1 expression of lungs exposed to crocidolite asbestos in vivo. Male Wistar rats were administered 1 mg or 2 mg crocidolite asbestos suspended in saline by a single intratracheal instillation and were sacrificed at 3 d, 1 wk, 1 mo, 3 mo, and 6 mo of recovery time. The expression of HO-1 was observed by Western blot analysis and immunostaining. Protein levels of HO-1 increased at from 3 d to 6 mo following intratracheal instillation of 2 mg crocidolite asbestos. The levels of HO-1 increased at 1 wk and 1 mo following intratracheal instillation of 1 mg crocidolite asbestos. Many HO-1-positive cells were found, particularly in the alveolar macrophages, during immunostaining. These findings suggest that HO-1 may be related to lung disorder induced by dust and therefore can act as a biomarker of lung injury due to dust exposure.
Stability of ferruginous bodies in human lung tissue following death, embalmment, and burial. R.F. Dodson, M.A. Atkinson, M. O'sullivan. 2005;17(14):789-95. PubMed · Publisher

Abstract

The identification of asbestos bodies in tissue sections is an indicator of past exposure to longer asbestos fibers. These structures are formed in lung tissue as a consequence of interactions with pulmonary macrophages resulting in the deposition of a ferroprotein (ferruginous) coating on the fiber. While the process of ferruginous body formation is known to take months in animal tissue, there is no published information on the stability of ferruginous bodies in tissue following death. The material assessed in the present study was obtained from lung material collected from an exhumed body approximately 8(1/2) mo after death, embalmment, and burial. Tissue sections were reviewed for the presence of asbestos bodies. Additional pieces of lung tissue were digested, with the digestate being evaluated by light microscopy for ferruginous bodies and by electron microscopy for uncoated asbestos fibers and core analysis of asbestos bodies. Classical ferruginous (asbestos) bodies were found in abundance in the tissue sections including in areas with fibrosis. The levels of uncoated asbestos fibers and classical appearing ferruginous bodies (asbestos bodies) were consistent with occupational levels of tissue burden. The data from this study indicate that ferruginous bodies remain morphologically stable within the tissue for months following death, embalmment, and burial. Thus the lung tissue from this exhumed individual was usable not only to pathologically confirm asbestosis but also to provide quantitative data of occupational exposure to asbestos.
Testing of fibrous particles: short-term assays and strategies. D. Bernstein, V. Castranova, K. Donaldson, et al. 2005;17(10):497-537. PubMed · Publisher
The biopersistence of Canadian chrysotile asbestos following inhalation: final results through 1 year after cessation of exposure. D. Bernstein, R. Rogers, P. Smith. 2005;17(1):1-14. PubMed · Publisher

Abstract

Chrysotile asbestos, a serpentine mineral, has been shown to be notably different from amphibole asbestos such as amosite, crocidolite, and tremolite in that chrysotile once inhaled is rapidly removed from the lung while the amphiboles persist. This has been demonstrated for three different chrysotile samples from Canada, the United States, and Brazil. The initial results of the inhalation biopersistence study on the Canadian chrysotile were reported earlier. This article presents the full results through 365 days after cessation of exposure. In order to fully understand the dynamics of the clearance of chrysotile from the lung, the study included a standardised inhalation biopersistence study following the recommendations of the European Commission (EC) Interim Protocol for the Inhalation Biopersistence of synthetic mineral fibers (Bernstein & Riego-Sintes, 1999) in which the lungs were digested to evaluate fiber content remaining. In addition, confocal microscopy was used to examine lungs in three dimensions to determine where and what size the remaining fibers were in the lung tissue. The results showed that Canadian chrysotile is cleared from the lung with a clearance half-time of 11.4 days for the fibers longer than 20 microm. Canadian chrysotile clears in a range similar to that of glass and stone wools. It remains less biopersistent than ceramic and special purpose glasses and considerably less biopersistent than amphibole asbestos. At 1 yr after cessation of exposure, no long (L>20 microm) chrysotile fibers remained in the lung. In contrast, with amosite asbestos there were 4 x 10 (5) long fibers (L>20 microm) remaining in the lungs at one year after cessation of exposure (Hesterberg et al., 1998). These results fully support the differentiation of chrysotile from amphiboles reported in recent evaluations of available epidemiological studies (Hodgson & Darnton, 2000; Berman & Crump, 2004).
Extrapolation of the carcinogenic potency of fibers from rats to humans. K. Rödelsperger. 2004;16(11-12):801-7. Review PubMed · Publisher

Abstract

In 1999 Berry published a model for mesothelioma incidence following fiber exposure. He concluded, that the influence of the solubility of fibers on the mesothelioma rate is 17 times higher in humans than in rats. This conclusion may be helpful for evaluating the carcinogenic risk from man-made vitreous fibers, but it had little influence on some recent discussions. It has been demonstrated using this model, that in an injection experiment with rats, fibers with elimination constants of 0.1/year and 1/year--which would approximately correspond to crocidolite and perhaps ceramic fibers--differ in their mesothelioma risk only by a ratio of 3.2:1. In contrast, for humans exposed continuously from age 20 to age 60 a risk ratio of 4,750:1 is obtained. This result may be helpful for the assessment of the human cancer risk e.g., from exposure to refractory ceramic fibers. However, uncertainty is large, since the life-span of rats is too low to measure the elimination rate of bio-persistent fibers sufficiently.
Patterns of histopathological change determined by the point counting method and its application for the hazard assessment of respirable dust. A. Ogami, Y. Morimoto, H. Yamato, et al. 2004;16(11-12):793-800. PubMed · Publisher

Abstract

We evaluate the morphometric point counting method (PCM) for qualitatively analyzing pulmonary inflammation and collagen deposits (i.e., fibrosis) in the assessment of the biological hazards of inhaled respirable particles at a realistic dose comparable to that of exposure in the work environment. Rats were exposed by intratracheal instillation to a 2-mg dose, which is close to the estimated overdose at which macrophage clearance is impared, of each of 3 kinds of particulate matter: crystalline silica, crocidolite asbestos, and titanium dioxide. The lung tissue was evaluated at 3 days, 1 wk, and 1, 3, and 6 mo after exposure. Digital images taken of the lung tissue after processing and staining of the lung sections were examined by the PCM under light microscopy. Evidence of inflammation along with progressive inflammatory changes occurred with crystalline silica and crocidolite, which are well-known hazardous particle types. In contrast, lung tissue from rats exposed to titanium dioxide particles demonstrated a decreasing pattern of histopathological change with increasing retention time. Differences in repair patterns of TiO(2) versus crocidolite and silica following the 2-mg dose exposure suggest that the PCM scoring system may be a useful and sensitive tool for qualitatively evaluating the biological hazards of new particle types, for which no toxicological information exists for low-dose exposure, by using the results from assessment of fibrogenic particle types (such as crocidolite and crystalline silica) as well as particle types with low toxicity (such as TiO(2)) as reference points.
Quantitative analysis of asbestos burden in a series of individuals with lung cancer and a history of exposure to asbestos. R.F. Dodson, D.R. Brooks, M. O'Sullivan, et al. 2004;16(9):637-47. PubMed · Publisher

Abstract

Asbestos is recognized as a lung carcinogen. In the present study, tissue from 20 individuals who died from lung cancer and who had a history of exposure to asbestos was evaluated for the presence of asbestos bodies and uncoated asbestos fibers. A digestion procedure was used to isolate the particulates from the tissue. The samples were evaluated by light microcopy to quantify the numbers of ferruginous bodies in the tissue. The uncoated fibers (which included all fibers equal to or greater than 0.5 microm) were analyzed by analytical transmission electron microscopy. Seventeen of the 20 cases were positive for ferruginous bodies (which were morphologically consistent with asbestos bodies). Five of these were found to have concentrations within the range used in our laboratory for the general population (<20 ferruginous bodies/g wet tissue). Nineteen of the 20 cases were found to have asbestos fibers in the higher magnification scan (either 16 K or 20 K). Some of the asbestos fibers identified were specific for the types of exposures that were reported. Most individuals in this study were found to have mixed populations of asbestos fibers in the lung tissue. This suggests that when there are exposures to products containing commercial asbestos there are likely exposures to dust containing noncommercial asbestos. A contrast exists in the dust burden within the lung of these individuals as compared to samples from the general population in that occupational or "occupational-like" exposures such as in these cases are often reflected by the presence of longer fibers of asbestos in the tissue.
The biopersistence of brazilian chrysotile asbestos following inhalation. D.M. Bernstein, R. Rogers, P. Smith. 2004;16(11-12):745-61. PubMed · Publisher

Abstract

With the initial understanding of the relationship of asbestos to disease, little information was available on whether the two different groups of minerals that are called asbestos were of similar or different potency in causing disease. Asbestos was often described as a durable fiber that if inhaled would remain in the lung and cause disease. It has been only more recently, with the development of a standardized protocol for evaluating the biopersistence of mineral fibers in the lung, that the clearance kinetics of the serpentine chrysotile have been shown to be dramatically different from those of amphibole asbestos, with chrysotile clearing rapidly from the lung. In addition, recent epidemiology studies also differentiate chrysotile from amphibole asbestos. The biopersistence studies mentioned have indicated that chrysotile from Canada and California clear rapidly from the lung once inhaled. However, variations in chrysotile mineralogy have been reported depending upon the region. This is most likely associated with variations in the forces which created the chrysotile fibers centuries ago. In the present study, the dynamics and rate of clearance of chrysotile from the Cana Brava mine in central Brazil was evaluated in a comparable inhalation biopersistence study in the rat. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 microm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and translocation and distribution within the lung. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 450 fibers/cm(3) longer than 20 microm in length present in the exposure aerosol. For the fiber clearance study (lung digestions), at 1 day, 2 days, 7 days, 2 wk, 1 mo, 3 mo, 6 mo, and 12 mo following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy (at the GSA Corp.) for total chrysotile fiber number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. This lung digestion procedure digests the entire lung with no possibility of identifying where in the lung the fibers are located. A fiber distribution study (with confocal microscopy) was included in order to identify where in the lung the fibers were located. At 2 days, 2 wk, 3 mo, 6 mo, and 12 mo postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and those fibers translocated to the broncho-associated lymphoid tissue (BALT) subjacent to bronchioles in rat lungs. While the translocation of fibers to the BALT and lymphatic tissue is considered important as in cases of human's with asbestos-related disease, there has been no report in the literature of pathological changes in the BALT and lymphatic tissue stemming from asbestos. Thus, if the fibers are removed to these tissues, they are effectively neutralized in the lung. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 microm were cleared with a half-time of 1.3 days, most likely by dissolution and breakage into shorter fibers. Shorter fibers were also rapidly cleared from the lung with fibers 5-20 microm clearing even more rapidly (T1/2 = 2.4 days) than those < 5 microm in length (T1/2 weighted = 23. days). Breaking of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were never found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. These results support the evidence presented by McDonald and McDonald (1997) that the chrysotile fibers are rapidly cleared from the lung in marked contrast to amphibole fibers which persist.
Comparative cytotoxicity study of rock wool and chrysotile by cell magnetometric evaluation. Y. Kudo, M. Watanabe, M. Okada, et al. 2003;15(13):1275-95. PubMed · Publisher

Abstract

Rock wool (RW), a type of man-made mineral fiber (MMMF), is a building material used as an asbestos substitute for heat insulation, fire resistance, and reinforcement. RW is included in group 3 of the IARC classification. In the present study, the cytotoxicity of RW was investigated by cell magnetometry, enzyme assay, DNA ladder detection, and electron microscopic morphological evaluation in comparison with chrysotile fibers (CF). Specimens were prepared by 18-h incubation of Fischer rat alveolar macrophages in the presence of RW fibers as the study material, CF as positive control, and phosphate-buffered saline (PBS) as negative control, together with a relaxation indicator, Fe3O4, except for morphological evaluation, followed by additional procedures of external magnetization and subsequent 20-min remanent magnetic field measurement for magnetometric evaluation, and macrophage DNA extraction for evaluating possible apoptosis by DNA ladder detection. In magnetometry, relaxation, a marker of cytotoxicity, was rapid in both the RW- and PBS-treated groups, while it was delayed in both the long and short CF-treated groups. Differences in percent lactate dehydrogenase (LDH) release between the RW-treated group and PBS-treated group were not significant, but those between the RW-treated group and short CF-treated group were statistically significant. A DNA ladder was not detected in any of the study groups. Electron micrographs showed that RW did not cause any change, but CF caused changes in macrophages. Thus, magnetometric measurements suggested no cytotoxicity of RW. We plan, in the future, to evaluate the safety of RW by magnetometric measurement and morphological observation of the lungs in in vivo inhalation experiments.
Comparison of Calidria chrysotile asbestos to pure tremolite: inhalation biopersistence and histopathology following short-term exposure. D.M. Bernstein, J. Chevalier, P. Smith. 2003;15(14):1387-419. PubMed · Publisher

Abstract

The differences between chrysotile asbestos, a serpentine mineral, and amphibole asbestos have been debated extensively. Many studies have shown that chrysotile is cleared from the lung more rapidly than amphibole. In order to quantify the comparative clearance of chrysotile and the amphibole asbestos tremolite, both fibers were evaluated in an inhalation biopersistence study that followed the European Commission recommended guidelines. In addition, the histopathological response in the lung was evaluated following the short-term exposure. This article presents the results of this study through 90 days after cessation of exposure. Following the termination of the study, a subsequent article will provide the complete results through 12 mo after cessation of exposure. In order to quantify the dynamics and rate by which these fibers are removed from the lung, the biopersistence of a sample of commercial grade chrysotile from the Coalinga mine in New Idria, CA, of the type Calidria RG144 and of a long-fiber tremolite were studied. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 microm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and the histopathological response. As the long fibers have been shown to have the greatest potential for pathogenicity, the aerosol generation technique was designed to maximize the number of long respirable fibers. The chrysotile samples were specifically chosen to have 200 fibers/cm3 longer than 20 microm in length present in the exposure aerosol. These longer fibers were found to be largely composed of multiple shorter fibrils. The tremolite samples were chosen to have 100 fibers/cm3 longer than 20 microm in length present in the exposure aerosol. Calidria chrysotile fibers clear from the lung more rapidly (T1/2, fibers L > 20 microm = 7 h) than any other commercial fiber tested including synthetic vitreous fibers. With such rapidly clearing fibers, the 5-day exposure would not be expected to result in any pathological change in the lung, and the lungs of animals that inhaled Calidria chrysotile showed no sign of inflammation or pathology and were no different than the lungs of those animals that breathed filtered air. Following this 5-day exposure to tremolite, the tremolite fibers once deposited in the lung parenchyma do not clear and almost immediately result in inflammation and a pathological response in the lung. At the first time point examined, 1 day after cessation of exposure, inflammation was observed and granulomas were already formed. By 14 days postexposure these microgranulomas had turned fibrotic, and by 90 days postexposure the severity of the collagen deposits had increased and interstitial fibrosis was observed in one of the rats. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and the amphibole tremolite. As Calidria chrysotile has been certified to have no tremolite fiber, the results of the current study together with the results from toxicological and epidemiological studies indicate that this fiber is not associated with lung disease.
Environmental sample correlation with clinical and historical data in a friction product exposure. J.L. Levin, M. O'Sullivan, R.F. Dodson. 2003;15(7):639-47. Case report PubMed · Publisher

Abstract

Asbestos has been widely used in the past as a component in friction products. A unique setting of dust exposure to such products occurs when individuals are involved with refabrication of the worn components. It is of interest whether asbestos fibers are released from friction materials in the use phase and the postlife phase or if the mineral fibers are converted to a nonasbestos form. In the present study, an individual whose primary work activity had centered on clutch refabrication was evaluated for possible dust-related diseases. Tissue analysis revealed the presence of large numbers of asbestos fibers as well as ferruginous bodies. These particulates were characterized as to composition as well as dimensions. Clutches of the type typically used by this individual were obtained and material was rinsed from their surface for comparative purposes. Materials that were freed from the surface and reviewed by analytical transmission electron microscopy were clearly identifiable as chrysotile asbestos. The composition of the clutch material was compared with the components found in the patient's lung tissue. The conclusion from this comparison was that individuals exposed to friction materials under similar circumstances should use appropriate caution. Appreciable exposure to asbestos can occur and this exposure can be sufficiently high to result in disease.
Man-made mineral fiber hazardous properties assessment using transgenic rodents: example of glass fiber testing. M.C. Bottin, J.C. Vigneron, R. Rousseau, et al. 2003;15(10):1017-27. PubMed · Publisher

Abstract

Transgenic BigBlue rats were exposed to CM 44 glass fibers (6.3 mg/m3) by nose only, 6 h/day for 5 days. Two endpoints were examined 1, 3, 14, 28, and 90 days following exposure: fiber biopersistence and mutations in lung DNA. The half-time of the fibers >20 microm was 12.8 days, and mutant frequencies of control and exposed rats were similar across all time points. The mutation spectra of both series were similar after 28 days of fixation time. These results showed that a glass fiber with a high clearance in the lung seems to not present any significant effect on mutagenesis on lung DNA and are in marked contrast to results for asbestos, which caused a twofold mutant frequency increase as described in a previous study.
The biopersistence of Canadian chrysotile asbestos following inhalation. D.M. Bernstein, R. Rogers, P. Smith. 2003;15(13):1247-74. PubMed · Publisher

Abstract

Chrysotile asbestos is often included with other asbestos materials in evaluation and classification. However, chrysotile is a serpentine with markedly different physical and chemical characteristics in comparison to amphiboles (e.g., crocidolite, amosite, tremolite). In contrast to amphiboles, which are solid, rodlike fibers, chrysotile is composed like a rope of many fine fibrils, which tend to unwind. In order to quantify the dynamics and rate by which chrysotile is removed from the lung, the biopersistence of a sample of commercial chrysotile from the Eastern Townships area of Quebec, Canada, labeled QS Grade 3-F, which is the longest commercial grade intended for textile use, was studied. As the long fibers have been shown to have the greatest potential for pathogenicity, the chrysotile samples were specifically chosen to have more than 200 fibers/cm3 longer than 20 micro m present in the exposure aerosol. This publication presents the results of this study through 3 mo postexposure. The study design included: (1) Fiber clearance (lung digestions): At 1 day, 2 days, 7 days, 14 days, 1 mo, 3 mo, and 12 mo (to be reported) following a 5-day (6 h/day) inhalation exposure, the lungs from groups of animals were digested by low-temperature plasma ashing and subsequently analyzed by transmission electron microscopy for total chrysotile fibers number in the lungs and chrysotile fiber size (length and diameter) distribution in the lungs. (2) Fiber distribution (confocal microscopy): This procedure was included in order to identify the location of the fibers in the lung. At 1 day, 2 days, 7 days, 14 days, 1 month, and 3 months (to be reported) postexposure, the lungs from groups of animals were analyzed by confocal microscopy to determine the anatomic fate, orientation, and distribution of the retained chrysotile fibrils deposited on airways and in the parenchymal region. Chrysotile was found to be rapidly removed from the lung. Fibers longer than 20 micro m were cleared with T(1/2) = 16 days, most likely by dissolution and disintegration into shorter fibers. The shorter fibers were also rapidly cleared from the lung, with fibers 5-20 micro m clearing even faster (T(1/2) = 29.4 days) than those <5 micro m in length. The fibers <5 micro m in length cleared at a rate (T(1/2) = 107 days) that is within the range of clearance for insoluble nuisance dusts. The breaking apart of the longer fibers would be expected to increase the short fiber pool and therefore could account for this difference in clearance rates. The short fibers were not found clumped together but appeared as separate, fine fibrils, occasionally unwound at one end. Short free fibers appeared in the corners of alveolar septa, and fibers or their fragments were found within alveolar macrophages. The same was true of fibers in lymphatics, as they appeared free or within phagocytic lymphocytes. Neutrophil-mediated inflammatory response did not occur in the presence of chrysotile fibers at the time points examined. Taken in context with the scientific literature to date, this report provides new robust data that clearly support the difference seen epidemiologically between chrysotile and amphibole asbestos.
The sensitivity of lavage analysis by light and analytical electron microscopy in correlating the types of asbestos from a known exposure setting. R.F. Dodson, M. O'Sullivan, D. Brooks, et al. 2003;15(5):461-71. PubMed · Publisher

Abstract

Lavage material was collected from 12 individuals whose work history included working in a cement manufacturing facility. The manufacturing processes of the facility included the use of crocidolite and chrysotile asbestos. Lavage material was prepared via digestion procedure and then analyzed for the presence of ferruginous bodies by light microscopy and for uncoated asbestos fibers by analytical transmission electron microscopy. A comparison was made as to the sensitivity between two analytical methods for linking a past exposure to a specific type of asbestos. The use of analytical transmission electron microscopy for identification of core material in the ferruginous bodies as well as for quantification of the uncoated asbestos fibers increased the sensitivity of the information obtained from lavage samples as necessary for confirming exposure in the past to specific types of asbestos.
Why are lung cancer rate trends so different in the United States and United kingdom?. P.N. Lee, B.A. Forey. 2003;15(9):909-49. PubMed · Publisher

Abstract

Over the period 1951-1995, lung cancer rates in men aged 35-74 yr more than doubled in the United States but declined slightly in the United Kingdom. In women, rates rose about sevenfold in the United States but only about threefold in the United Kingdom. To investigate whether these very different trends in lung cancer risk could be explained by smoking habits, trends in smoking were compared in the two countries and a multistage model was used to predict lung cancer rates from detailed data on age of starting and stopping smoking, amount smoked per smoker, and sales-weighted average tar levels. In both countries, there was a similar switch to filter cigarettes, reduction in tar levels and the average age of starting to smoke, and decline in prevalence of smoking in women aged under 50 yr and in men. Although some differences were evident, most notably in older women where prevalence of smoking and consumption per adult has increased more in the United States, these trends do not appear to explain the markedly different trends in lung cancer, evident in both sexes and all age groups. The multistage analyses confirmed these tentative conclusions-the differing trends in smoking in the two countries could not explain the markedly differing trends in lung cancer. Lung cancer trends in the United Kingdom were found to be clearly more favorable than expected on the basis of smoking trends, while trends in the United States were less favorable. In sensitivity analyses, these conclusions were found not to be materially dependent on the precise methods used, including whether tar reduction was or was not assumed to be beneficial. The explanation for these findings must lie in changes over time, differing in the two countries, in aspects of smoking not considered in these analyses and/or in exposure to other risk factors. Evidence relating to a number of possible such smoking variables (including type of tobacco, curing, use of pesticides and additives, and butt length) or other risk factors (including air pollution, radon, asbestos, obesity, and marijuana) is discussed, but no clear explanation of the findings is offered. Further research is urgently needed to investigate the causes of these apparently anomalous trends in lung cancer and in smoking habits. Criticism is also presented of the views recently expressed by the authors of NCI Monograph 13 that tar reduction has been ineffective in lowering lung cancer risk and that trends in lung cancer in the United States fit in well with trends in smoking habits.
Antioxidant defense mechanisms and the toxicity of fibrous and nonfibrous particles. K.E. Driscoll, J.M. Carter, P.J. Borm. 2002;14(1):101-18. Review PubMed · Publisher

Summary

This narrative review examined how antioxidant defenses of the respiratory tract relate to the toxicity of inhaled fibrous and nonfibrous particles, and what species differences in these defenses might mean for risk assessment. The authors described the lung's enzymatic and nonenzymatic antioxidants. They summarized in vitro, animal and human studies indicating that particles act partly through reactive oxygen species, including crystalline silica, crocidolite and chrysotile asbestos, ambient air particles, hard metal and combustion particles. They reviewed evidence that particle exposure induced antioxidant enzymes such as manganese superoxide dismutase, that antioxidants reduced asbestos effects in cultured cells and in rats, and studies of antioxidants in coal miners. Comparative studies reported markedly lower lung catalase in rats than in other species, and one found antioxidant enzyme levels most similar in humans and hamsters. The authors also presented data in which rats and hamsters received quartz by intratracheal instillation at 0.2, 2 or 20 mg/kg and were examined 7 days later. Hamsters had higher basal lung catalase and metallothionein and induced them more strongly. Rats showed greater release of reactive oxygen and nitrogen species, more tissue injury and more cell proliferation. Similar findings were reported for carbon black. The authors concluded that the rat may be an especially sensitive species to oxidative injury from particles and that understanding antioxidant capacity could help extrapolation from animals to humans.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Appropriate in vitro test conditions for genotoxicity testing of fibers. G. Speit. 2002;14(1):79-90. Review PubMed · Publisher

Abstract

With the exception of asbestos fibers, little information is available on genotoxicity testing of fibers (i.e., respirable-sized, fiber-shaped particulates, RFP). In contrast to standard genotoxicity testing of soluble substances, fibers bring about specific problems. Test results can be influenced by fiber dimensions, surface properties, and biopersistence. The mechanisms of fiber-induced genotoxicity are not yet clear, but direct interaction with the genetic material and indirect effects via production of reactive oxygen species (ROS) have been proposed. Asbestos did not significantly induce gene mutations in bacterial and mammalian systems but led to a clear induction of structural and numerical chromosome aberrations in cultured mammalian cells. It is the purpose of this article to critically review positive in vitro genotoxicity data obtained for asbestos in the comet assay, the chromosome aberration test, and the micronucleus test and to identify the test conditions that are specifically required for the detection of asbestos-induced genotoxicity. It is concluded that appropriate cell systems are available for testing fiber-induced genotoxicity. Fiber samples have to be well characterized and phagocytosis and cytotoxic effects have to be determined for the correct interpretation of genotoxicity test results. A combination of the micronucleus test and the comet assay using continuous treatment (without exogenous metabolic activation) seems to be well suited to detect genotoxic activity of asbestos fibers with high accuracy. Further investigations are needed to shown whether this approach can be recommended for genotoxicity testing of fibers in general.
Mechanisms of genotoxicity of particles and fibers. R.P. Schins. 2002;14(1):57-78. Review PubMed · Publisher

Abstract

With regard to genotoxicity testing and cancer risk assessment, particles and fibers form a rather specific group among all toxicants. First, the physicochemical behavior of fibrous and nonfibrous particles is usually very different from that of nonparticulate, chemical carcinogens. Reactive oxygen species (ROS) are believed to play a major role in primary genotoxicity of particles, which may derive from their surface properties, the presence of transition metals, intracellular iron mobilization, and lipid peroxidation. Other aspects relevant to primary genotoxicity are particle size, shape, crystallinity (e.g., silica), and solubility, and may also include particle uptake, interaction with cell division machinery (e.g., asbestos), and the presence of mutagens carried with the particle (e.g., diesel exhaust particles, DEP). Excessive and persistent formation of ROS from inflammatory cells is considered as the hallmark of the secondary genotoxicity of nonfibrous and fibrous particles. Since lung inflammation is known to occur and persist only at sufficient particle dose, this secondary pathway is considered to contain a threshold (Greim et al., 2001). Identification of (mechanisms of) particle genotoxicity has been/can be achieved via (1) acellular assays, (2) in vitro tests, (3) in vivo studies, usually in mice or rats, and finally (4) biomarker studies in humans with (occupational) exposure. The significance of acellular assays and biomarker studies for risk assessment is limited, but has provided some mechanistic insights (e.g., in oxidant generating properties of quartz and asbestos) and may also contribute to hazard identification. In vitro studies have lead to identification of primary genotoxic properties of particles, whereas recent in vivo studies provide further support for the correlation between particle-induced lung inflammation and secondary genotoxicity. Proper risk assessment of particles necessitates identification of the relative impact of primary versus secondary genotoxicity in realistic exposure conditions. However, since it is impossible to discern between primary and secondary genotoxicity with current in vivo tests, concomitant in vitro assays are required to determine primary genotoxicity. In vivo tests should ideally be designed using different doses to allow dose-effect analysis for both inflammation and genotoxicity.
Particle toxicology: from coal mining to nanotechnology. P.J. Borm. 2002;14(3):311-24. Historical article · Review PubMed · Publisher

Abstract

Particle research has been historically closely connected to industrial activities or materials, such as coal, asbestos, man-made mineral fibers, and more recently ambient particulate matter (PM). It is the purpose of this review to combine insights and developments in particle toxicology with the historical context of exposure and organizations sponsoring such research in Europe. In supporting research on particle-induced respiratory effects and mechanisms, research programs of the European Community on Steel and Coal (ECSC) have played a tremendous role. Current particle research in Europe is dominated by PM, and funded by the World Health Organization (WHO), European Union Framework programs, and the Health Effects Institute (HEI). Differences between historical and current research in particle toxicology include the exposure concentrations, particle size, target populations, endpoints, and length of exposure. Inhaled particle effects are no longer confined to the lung, since particles are suggested to translocate to the blood while lung inflammation invokes systemic responses. Finally, the particle size and concentrations have both been reduced about 100-fold from 2-5 mg/m3 to 20-50 mg/m3 and from 1-2 microm to 20-100 nm (ultrafine) as domestic fuel burning has decreased and vehicle sources have increased and attention has moved from coal mining industry to general environment. There is, however, a further occupational link to nanotechnology, which continuously produces new materials in the ultrafine range. Although inhalation exposure is considered to be minimal in this technology, some particles are produced to be used for carrier purpose in medical applications. Based on our current knowledge of particle toxicology, it is highly desirable that toxicology and technology are linked in this extremely rapid developing area, to learn more about potential risks and also to develop knowledge on the role of surface and size in particle toxicity.
Toxicokinetics and effects of fibrous and nonfibrous particles. G. Oberdörster. 2002;14(1):29-56. Review PubMed · Publisher

Abstract

Chronic inhalation of fibrous and nonfibrous particles by rats at high concentrations results in lung tumor formation if the particles are poorly soluble in the lung. Even rather benign nonfibrous particles such as TiO(2) produce this result. One significant change during a chronic inhalation exposure of poorly soluble particles of low cytotoxicity (PSP) is an impairment of normal clearance mechanisms in the alveolar region of the lung in rats, resulting in a continued buildup to high lung burdens accompanied by chronic alveolar inflammation, fibrosis, and mutational events. Since these are obviously high-dose effects, questions about their extrapolation to humans exposed to much lower concentrations have been raised. Results of key studies reported for chronic inhalation of PSP in rats indicate that mechanisms of PSP-induced lung tumors at high doses do not operate at low dose levels. Furthermore, the existence of two thresholds can be postulated: One is a dosimetric threshold for the endpoint alveolar macrophage-mediated clearance, which is related to lung particle overload. The other is a mechanistic threshold for the endpoint mutation, which is determined by the level of antioxidant defenses to counterbalance reactive oxidant species released by activated inflammatory cells. A no-observed-adverse-effect level (NOAEL) could therefore be based on avoiding alteration of the toxicokinetic of the particles such that the lung burdens stay below the dosimetric threshold. The suggestion that PSP-associated organic compounds (e.g., diesel particulate matter) contribute to the lung tumor responses in rats observed in chronic inhalation studies is not supported by experimental data from in vivo studies. It can be concluded that high-dose rat lung tumors due to PSP should not be used for low-dose extrapolations, and no significant contribution to human lung cancer risk can be predicted from levels of PSP below lung overload. With respect to the pulmonary toxicokinetics of inhaled fibrous particles, the biopersistence of long fibers (>20 microm) which cannot be phagocytized by alveolar macrophages is a key parameter related to long-term carcinogenic effects. Long fibers with a very low biopersistence should not be considered as carcinogenic. Since the clearance kinetics of fibers can generally be described by a biphasic or multiphasic pattern-fast initial and slow final phase-it is essential that the slow phase of the retention kinetics of fibers longer than 20 microm is considered in a biopersistence assay. Based on the results of such assay, fibers can be classified into one of two categories: a biopersistent fiber that cannot be dissolved in the lung within an acceptable time period; or a biosoluble fiber when even long nonphagocytizable fibers will be disappearing rapidly from the lung. However, in addition to biopersistence, it should be mandatory to evaluate fiber toxicity in an appropriate assay relative to a fiber whose long-term effects are well known. Moreover, for organic fibers it is likely that different rules may have to be established for characterization of their toxic and carcinogenic potential.
Tumorigenicity of cellulose fibers injected into the rat peritoneal cavity. R.T. Cullen, B.G. Miller, S. Clark, et al. 2002;14(7):685-703. PubMed · Publisher

Abstract

Cellulose fibers, along with many other organic fibers, are durable. Therefore, if inhaled, they have the potential to persist within the lung, and may then cause disease. Here we report the effects of injecting high-purity cellulose fibers into the abdominal cavity of rats. A respirable fraction of cellulose fiber was collected from an aerosol of a thermo-mechanically-processed wood pulp. A sample of respirable crocidolite asbestos, known to produce mesotheliomas in rats, was used as a positive control. Total doses of 10(6), 10(7), 10(8), or 10(9) WHO fibers were injected intraperitoneally as 3 weekly aliquots. A negative control was provided by phosphate-buffered saline used to suspend the fibers for injection. There were 50 rats per treatment group except for the 10(8) and 10(9) fibers crocidolite groups which were reduced to 26 rats because of the expectation of high tumor incidence in these groups. The two higher doses of crocidolite asbestos caused greatly reduced survival compared to the saline controls. With cellulose there was a much less marked effect on survival. In the highest dose cellulose group, multiple large nodules (granulomas) and widespread adhesions (bands of new tissue connecting organs to each other and to the abdominal wall) were present in all animals. Granulomas were not observed in the 10(9) fibers crocidolite group. More than 80% of animals in the 10(8) and 10(9) crocidolite asbestos groups had mesotheliomas, a type of tumor sometimes observed in people exposed to asbestos. In contrast, there were only 2 animals in the cellulose groups with mesothelioma tumors, 1 in the 10(7) and 1 in the 10(8) groups. However, 9 (18%) of the 10(9) cellulose group had malignant tumors that, in contrast to the usual pattern of mesothelioma development following treatment with mineral fibers in rats, showed no obvious involvement of mesothelial tissues, were not associated with blood-stained ascites fluid, and were thus classified as sarcomas. This study has demonstrated that a high dose of cellulose fibers is capable of producing tumors when injected into the abdominal cavity of rats.
A Comparison of Pleural Mesotheliomas Induced by Asbestos or SV40 Virus in Syrian Golden Hamsters. E.E. McConnell, M. Carbone. 2000;12 Suppl 3:173-81. PubMed · Publisher

Abstract

Pleural mesotheliomas are a well-known consequence of exposure to asbestos in both humans and animals. However, there are cases of mesothelioma in humans for which there is little or no known exposure to asbestos. Mesotheliomas have also been produced in hamsters infected with simian virus 40 (SV40), a contaminant of early polio vaccines, which was shown to replicate in individuals inoculated with the vaccine. Recently, wild-type SV40 has been detected in human mesotheliomas as well as other types of neoplasms. Because the tumors were induced with such dissimilar agents, we evaluated mesotheliomas produced in hamsters after intrapleural injection of SV40 compared to those produced after inhalation exposure to amosite asbestos to see if there were differences in the development and morphology of the tumors. Although the mesotheliomas produced by both agents were clearly of mesothelial origin based on standard morphological criteria, there were clear differences. The SV40-induced tumors occurred with a short latency period, were large multicentric lesions with pleural effusion that always caused death within 3 to 6 mo, and were largely composed of small round cells growing in a uniformly tubulopapillary pattern with many areas of sarcomatous change. They had a minimal amount of stroma and tended to invade the adjacent tissues. The unaffected pleura showed no evidence of fibrosis. In contrast, the mesotheliomas induced by asbestos occurred much later (most after 18 mo), were rarely (<10%) the cause of death, and were typically very small with little evidence of pleural effusion. While they also had a tubulopapillary pattern, they were composed of larger cells with more abundant cytoplasm and sarcomatous change was rare. The adjacent pleura typically showed marked evidence of fibrosis and local invasion was rarely encountered. Whether these striking morphological differences between SV40- and asbestos-induced mesotheliomas in hamsters have a correlate in humans is not known. It would be useful to conduct a similar comparison of mesotheliomas from humans known to have been exposed to high levels of asbestos to those with no known exposure to see if similar morphological differences exist.
Asbestos Fiber Type and Length in Lungs of Chrysotile Textile and Production Workers: Fibers Longer than 18 μm. B.W. Case, A. Dufresne, A.D. McDonald, et al. 2000;12 Suppl 3:411-8. PubMed · Publisher

Abstract

Excess lung cancer risk for a cohort of chrysotile textile plant workers was many times the risk observed in a cohort of chrysotile miners/millers. The latter had greater exposure to chrysotile/tremolite. A previous lung burden study confirmed this excess exposure in miners/millers and showed little difference in fiber length. Selection of too short a fiber length cut-off (5 µm or more) in the previous study could have masked differences in lung-retained fiber length. In this follow-up, we counted only those intrapulmonary fibers exceeding 18 µm in length. Lung fiber concentration and dimension were assessed by transmission electron microscopy (TEM) and energy-dispersive x-ray spectrometry (EDS) for autopsy samples from 64 textile workers and 43 chrysotile miners and millers. These long fibers were significantly more concentrated in the lungs of chrysotile miners and millers, consistent with their greater exposure. However, when only these longest fibers were compared, there was a somewhat greater mean and median intrapulmonary fiber length for chrysotile textile workers (mean fiber length, all fiber types combined, 25.2 ± 10.2 µm vs. 22.9 ± 6.6 µm in miners/millers, < .001; medians 21.6 vs. 20, p < .05). Despite their lesser apparent lung cancer risk, chrysotile, tremolite, total amphibole, and total long fiber asbestos concentrations were all highest in the lungs of miners/millers. Twenty-two of 64 textile workers had lung content of crocidolite and/or amosite (32.5% of 508). These amosite/crocidolite fibers were present in the lungs of workers who ceased employment prior to the first use of such fibers recorded in this industry. The results suggest that (I) asbestos fiber length differences cannot explain the difference in lung cancer risk excess and slope between cohorts and (2) the experience of textile workers should not be used to assess risk of lung cancer in miners, cement workers, and friction product workers, regardless of fiber type.
Asbestos-Related Pleural Thickening is Independently Associated With Lower Levels of Lung Function and with Shortness of Breath. E. Algranti, J.B. Freitas, E.M. Mendonça, et al. 2000;12 Suppl 3:251-60. PubMed · Publisher

Abstract

This study investigated the relative contribution of asbestos-related pleural thickening (PT) to lung function indices and to respiratory symptoms. A group of 828 former asbestos cement workers enrolled in a cross-sectional and cohort study of respiratory morbidity and submitted to a detailed occupational history, respiratory symptoms questionnaire, spirometry, postero-anterior chest x-ray, and high-resolution computed chest tomography (HRCT). Asbestos exposure was assessed by years of exposure (a semi-quantitative method), cumulative exposure, and latency time from first exposure. Smoking was assessed in pack-years. PT and asbestosis were assessed according to HRCT criteria. Statistical analysis included descriptive analysis, univariate and multivariate analysis of variance for comparisons of factors related to PT, stepwise multiple regression analysis for continuous dependent variables, and logistic regression analysis for dichotomous dependent variables. Mean age was 51.4 (SD 10.5) years, mean years of exposure 12.4 (SD 8.8), mean cumulative exposure 79.9 (SD 68.5), and mean latency time 25.2 yr (SD 10.4). Of the 828, 238 (28.7%) were smokers, 288 (34.8%) former smokers, and 302 (36.2%) nonsmokers. PT was present in 246 (29.7%) and asbestosis in 74 (8.9%); 97 (11.9%) had shortness of breath of Grade III or more. PT subjects had lower height-adjusted forced vital capacity (FVC) and forced expiratory volume in I s (FEV1) and lower FEV1/FVC% (p < .00001 for all). Variables significantly related to PT were age (p < .000 1), years of exposure (p < .0000 1), cumulative exposure (p < .00001), latency time (p < .00001), pack-years (p < .0000 1), and asbestosis (p < .00 1). In a multiple stepwise regression model, after controlling for confounders, height adjusted FEV1 and FVC were in versely and significantly associated with PT, mainly when associated with asbestosis. A logistic regression model with shortness of brea th as the dependent va riable, con trolled for confounders, showed that PT was significa ntly associated with the symptom, even without asbestosis. In conclusion, PT is independently associated with lower va lues of FEV1 and FVC. PT is also independently associated with an increased risk of shortn ess of breath report. PT should be considered as a disease for clinical follow up and for compensa tion claims.
Cell Signaling in Mesothelial Cells by Asbestos: Evidence for the Involvement of Oxidative Stress in the Regulation of the Epidermal Growth Factor Receptor. S.P. Faux, C.E. Houghton. 2000;12 Suppl 3:327-36. PubMed · Publisher

Abstract

Asbestos has been shown to stimulate the mitogen-activated protein kinase signaling cascade after autophosphoryiation of the epidermal growth factor recptor (EGF-R), an event important in regulating the response of cells to extracellular signals. In studies reported here, we have examined whether mineral fibers with known carcinogenicity can be discriminated from nonpathogenic fibers by their ability to upregulate expression of EGF-R protein in mesothelial cells. Crocidolite and erionite, two fibrous preparations known to induce mesothelioma, increased expression of EGF-R protein in a time- and dose-dependent manner, whereas milled (nonfibrous) crocidolite and chrysotile asbestos, two preparations with much less or no ability to induce mesothelioma, did not. Intense patterns of EGF-R protein expression were linked to mesothelial cells phagocytosing long fibers as observed by phase-contrast microscopy. To determine the importance of EGF-R expression in these cells, we assessed downstream signaling events in rat pleural mesothelial (RPM) cells by looking at the induction of activator protein-1 (AP-I), a transcription factor that controls the transition to S phase in the cell cycle, leading to cell proliferation. Crocidolite induced AP-I in RPM cells in a dose-dependent manner, and this induction of AP-I in RPM cells was inhibited by coincubation with tyrphostin AG 1478, a potent inhibitor of the EGF-R. To examine the mechanism of induction of EGF-R in RPM cells by asbestos, RPM cells were treated with crocidolite in the presence and absence of the antioxidant N-acetylcysteine (NAC). Reduced glutathione (GSH) was examined as a marker of oxidative stress and the expression of EGF-R protein was measured. Crocidolite asbestos caused a dose-dependent depletion of GSH in RPM cells, and the presence of NAC ameliorated the expression of EGF-R protein by crocidolite. Our data suggest that carcinogenic fibers induce EGF-R via a mechanism involving oxidative stress initiating cell signaling cascades in mesothelial cells leading to cell proliferation and carcinogenesis.
Differential Display Analysis of Fiber-Induced Carcinogenesis in Rat: Clue for Involvement of Integrin-Mediated Signal Transduction. H. Sandhu, H. Olbrück, J. Abel, et al. 2000;12 Suppl 3:337-43. PubMed · Publisher

Abstract

In this study, mRNA expression patterns during mesothelioma carcinogenesis in the peritoneal cavity were investigated. To this purpose, the mRNA expression patterns of fiber-induced mesothelioma and of fiber-treated tissues were compared to untreated tissues, respectively. Suppression subtractive hybridization (SSH) and an array hybridization assay were used to perform differential display analyses. Genes found to be expressed differentially mainly represent proteins of signal transduction pathways and regulatory proteins of the cell cycle. The genes for components of the AP-1 transcription factor, c-jun, c-fos, and fra-1 (fos-related antigen-1) are upregulated in nontumorous tissue treated with asbestos. These data confirm in vivo the involvement of AP-I expression as response to fiber treatment. In addition, osteopontin, zyxin, and integrin-linked kinase were upregulated in tumors and in treated tissues. These genes code for proteins involved in the signal transduction from the extracellular matrix to the nucleus. Using integrin-specific inhibitors, the apoptotic effects of crocidolite fibers could be suppressed significantly. From these results we hypothesize that direct effects of the fibers on the target tissue are mediated by interaction of the fibers with the extracellular matrix molecules.
Effects of Crocidolite Fibers on the Peritoneal Mesothelium of Rats. K. Unfried, H. Sandhu, C. Schürkes, et al. 2000;12 Suppl 3:149-55. PubMed · Publisher

Abstract

The assay of intraperitoneal (ip) injection to rats was used as experimental system to study the mechanisms of carcinogenic effects of fibrous dusts. With this test system, fibers were shown to induce mesothelioma in the peritoneal cavity. Although the data of the ip assay are discussed controversially in terms of risk assessment, it is a valuable tool to investigate the molecular mechanisms of mesothelioma carcinogenesis in vivo. This test system allows one to investigate both the effects of fibers on signal transduction and the genotoxic potential of fibers. On the level of mRNA expression, different stages of fiber-induced tumor development in the peritoneal space were examined using differential display techniques. Genes of signal transduction pathways are mainly affected by the fiber treatment; for example, the activation of genes for the AP-1 transcription factor could be observed in the tissues of the peritoneal cavity. Thus, our in vivo data confirm the findings reported from cell culture systems. Moreover, our results from the differential display assays reveal that genes involved in the integrin-linked signal transduction are upregulated. In addition, the ip assay can be applied to transgenic animals to perform mutagenicity testing. Using the Big Blue transgenic animal system, we provide data of a significant increase in mutation frequency after treatment with crocidolite asbestos.
Estimation of dissolution rate from in vivo studies of synthetic vitreous fibers. W. Eastes, R.M. Potter, J.G. Hadley. 2000;12(11):1037-54. PubMed · Publisher

Abstract

Although the dissolution rate of a fiber was originally defined by a measurement of dissolution in simulated lung fluid in vitro, it is feasible to determine it from animal studies as well. The dissolution rate constant for a fiber may be extracted from the decrease in long fiber diameter observed in certain intratracheal instillation experiments or from the observed long fiber retention in short-term biopersistence studies. These in vivo dissolution rates agree well with those measured in vitro for the same fibers. For those special types of fibers, the high-alumina rock wool fibers that could not be measured in vitro, the method provides a way of obtaining a chemical dissolution rate constant from an animal study. The inverse of the in vivo dissolution rate, the fiber dissolution time, correlates well with the weighted half life of long fibers in a biopersistence study, and the in vivo dissolution rate may be estimated accurately from this weighted half-life.
Genotoxicity Versus Carcinogenicity: Implications from Fiber Toxicity Studies. T.K. Hei, A. Xu, D. Louie, et al. 2000;12 Suppl 3:141-7. PubMed · Publisher

Abstract

Although the association between exposure to asbestos fibers and the development of lung cancer and mesothelioma has been well established in humans, the carcinogenic potential of other natural and man-made fibers/particles is not clear. Various in vitro genotoxicity studies have been employed to assess their in vivo carcinogenic potential. Studies using mammalian cell models have suggested that fiber dimensions, surface properties, physical durability, and cell and tissue responses are important criteria for the carcinogenicity of the fibers. Studies using oncogenic transformation as an endpoint have shown that asbestos fibers can induce malignantly transformed foci in certain rodent cells and that oxygen radicals are important in the toxic, oncogenic transforming, and mutagenic effects of asbestos fibers. The mutagenicity of asbestos in mammalian cells have been demonstrated using several model systems that can detect large multilocus deletions. These findings provide a direct link between chromosomal abnormalities that have frequently been demonstrated in fiber-exposed human and rodent cell lines and carcinogenicity in vivo. Although asbestos has not been shown to malignantly transform primary human epithelial cells, it can induce neoplastic conversion of immortalized human bronchial epithelial cells in a stepwise fashion and provides a unique opportunity to assess the molecular alterations associated with each stage of the neoplastic process.
Hyperplastic and Neoplastic Changes in the Lungs of Rats Treated Concurrently with Chrysotile Asbestos and N-Nitrosoheptamethyleneimine. P.T. Harrison, J.A. Hoskins, R.C. Brown, et al. 2000;12 Suppl 3:167-72. PubMed · Publisher

Abstract

This study investigated the combined effect in rat lungs of simultaneous exposure to chrysotile asbestos and N-nitrosoheptamethyleneimine (NHMI), with the objective of determining the potential for chrysotile to promote or otherwise enhance the pathological responses to this potent rodent lung carcinogen. Groups of 15 or 20 male and female animals were treated with 0, 3, or 10 mg kg(-1) NHMI subcutaneously, once a week for 10 wk, plus either clean air (control) or 50 mg m(-3) chrysotile by nose-only inhalation for 4 wk. A broad range of pulmonary metaplastic, hyperplastic, and neoplastic lesions was observed. Effects were more marked in male than in female animals. NHMI treatment increased the incidence of hyperplastic lesions, with apparent augmentation by chrysotile exposure (not statistically significant). Similarly, a "promoting" effect of chrysotile in the induction of lung tumors was observed, with all but 2 of the 11 primary tumors detected being in animals treated with both NHMI and asbestos. However, this apparent interaction was again not confirmable statistically, probably because of the low number of observed tumors (stemming from premature termination of the experiment). The study results are in line with those of similar previous studies, which found a higher incidence of hyperplastic and neoplastic changes in animals treated with both nitrosamine and asbestos than in those given nitrosamine alone. It is proposed that the method described (with minor modification) could be used to investigate either (1) the ability of other inhaled particles to augment NHMI carcinogenicity, or (2) the propensity of other chemical carcinogens to interact with asbestos in the production of pulmonary neoplasms.
Inhalation of Asbestos Fibers and Consequent Expression of Peptide Growth Factors. A.R. Brody. 2000;12 Suppl 3:245-50. PubMed · Publisher

Abstract

It would be impossible to completely review this broad topic in the space and time allowed, lust as we must make choices when focusing on a research topic, this brief overview of particles and fibrosis deals with a small corner of our current thinking on the molecular mechanisms through which inhaled particles mediate fibroproliferative lung disease. At some point, there must be a common pathway of action because the fundamental process after any exposure involves fibroblast proliferation and production of extracellular matrix, that is, scar tissue. Thus, if we can understand how to control the fibroblast cell cycle and those genes that code for matrix components, it may be possible to develop effective therapeutic modalities for pulmonary fibrosis where none now exist. To control cell cycle and matrix genes that are expressed due to particle exposure, investigators have focused on certain peptide growth factors. The genes that code for these factors as well as the genes and oncogenes that are expressed when the peptides bind to their cognate receptors offer the best opportunities for understanding the molecular mechanisms of particle-induced lung fibrosis. As an example, mice with the genes knocked out for both the 55- and 75-kD receptors for tumor necrosis factor-alpha (TNF-α) are protected from the fibrogenic effects of inhaled asbestos and silica. Expression of other peptide growth factors in these animals is reduced, leading to a central working hypothesis, that TNF-α is a "master switch" that controls the expression of other more downstream factors that mediate components of the fibrogenic process. There is ample evidence of TNF-α expression in animal models and in populations of dust-exposed workers to support this postulate. In addition, it appears that transforming growth factor beta (TGF-β) is the primary peptide that controls production of extracellular matrix. Blocking of TGF-β expression in animal models prevents fibrosis, and the use of specific antisense RNA blocks both TGF-β and collagen gene expression in primary lung fibroblasts. Conversely, an adenovirus vector that transduces expression of TGF-β to the bronchiolar-alveolar epithelium induces diffuse fibrogenesis in rats and mice. Thus, particle-induced pulmonary fibrosis is a complex process that will be understood only after we dissect and elucidate the signal transduction pathways that control growth factor and matrix gene expression. The emerging technologies for developing transgenic and knockout mice, viral vectors for gene transduction, antisense approaches, and microarray gene analysis will finally allow us to accomplish these goals.
Investigations of DNA Damage Produced by Asbestos Fibers in Rat Pleural Mesothelial Cells. M.C. Jaurand. 2000;12 Suppl 3:183-7. PubMed · Publisher

Abstract

Asbestos fibers have long been considered nongenotoxic because of the absence of point asbestos-treated cells mutations in several assays. More recently, some studies have demonstrated that various kinds of DNA damage were observed in asbestos-treated cells, namely, base hydroxylation, DNA adducts, and DNA breaks. The occurrence of DNA breakage has been mostly suggested by indirect methods. We investigated DNA damage produced by Rhodesian chrysotile fibers in a model of normal rat pleural mesothelial cells (RPMC) developed in our laboratory, by different approaches. DNA breakage and repair of DNA damage were evidenced by the enhancement of the activity of poly(ADP)ribose polymerase (PARP) and of unscheduled DNA synthesis, and were suggested by cell cycle arrest in asbestos-exposed RPMC. In growing cells, a cell cycle arrest was observed at the G1-S transition. DNA breakage was also demonstrated by the formation of comets in single-cell gel electrophoresis (SCGE) assay. The results showed that comets were generated by asbestos, as assessed by the significant increase in mean tail length and mean tail moment after exposure to asbestos. In RPMC-TSV40 (i.e., RPMC in which the protein was p53 inactivated by infection with a retroviral recombinant encoding the large T antigen of the SV40 virus), the comet parameters were moderately enhanced. Regarding previous results of an impairment of DNA repair in RPMC-TSV40, the SCGE results suggest that chrysotile caused DNA breakage in both RPMC and RPMC-TSV40. Moreover, these findings lead to the hypothesis that DNA repair was impaired in RPMC-TSV40.
Lung Biopersistence and in Vitro Dissolution Rate Predict the Pathogenic Potential of Synthetic Vitreous Fibers. T.W. Hesterberg, G.A. Hart. 2000;12 Suppl 3:91-7. PubMed · Publisher

Abstract

Here we review the past decade of research on inorganic fiber toxicology, which demonstrates that fiber biopersistence and in vitro dissolution rate correlate well with fiber pathogenicity. Test fibers for these studies included eight synthetic vitreous fibers (SVFs)-refractory ceramic fiber (RCF1), four fiber glasses (FCs), rock wool, slag wool, HT stone wool-and two asbestos types (crocidolite and amosite). Fiber toxicology and biopersistence were investigated using rodents exposed by inhalation. To evaluate chronic inhalation toxicity, rodents were exposed nose-only to ∼ 100 fibers >20 µm in length (F > 20 µm)/cm(3), 6 h/day, 5 days/wk, for 2 yr (rats) or 1½ yr (hamsters). To evaluate lung biopersistence, rats were exposed nose-only for 5 days to fiber aerosol; lung burdens were then analyzed during 1 yr postexposure. In vitro dissolution rate was evaluated in a flow-through system using physiological solutions that mimic the inorganic components of extra- and intracellular lung fluids. The 10 test fibers encompassed a range of respiratory toxicities, from transient inflammation only to carcinogenesis. Lung clearance weighted half-times (WT½) for F > 20 µm were 6-15 days for stonewool, building insulation FCs, and slag wool; 50-80 days for rock wool, 2 special-application FCs, and RCFI; and >400 days for asbestos. WT½ correlated with pathogenicity: The rapidly clearing fibers were innocuous (insulation FCs, slag wool, and stonewool), but the more biopersistent fibers were fibrogenic (rock wool) or fibrogenic and carcinogenic (special-application FCs, RCFI, amosite and crocidolite asbestos). In vitro dissolution rates (k dis= ng/cm(2)/h) of the 10 fibers at pH 7.4 or 4.5 ranged from < 1 to >600. Fibers that dissolved rapidly in vitro also cleared quickly from the lung and induced only transient inflammation in the chronic studies. In contrast, fibers that dissolved slowly in vitro were biopersistent in the lung and tended to induce permanent pathogenicity. Other in vitro studies of fiber degradation suggest that, in addition to fiber dissolution, fiber leaching and subsequent transverse breakage may also be important mechanisms in lung biopersistence and hence pathogenicity. The validity of using lung biopersistence for predicting the potential pathogenicity of SVFs is confirmed by this research. The research also supports the use of in vitro fiber degradation at pH 7.4 and/or pH 4.5 as an indicator of SVF potential pathogenicity.
Mechanisms of action of poorly soluble particulates in overload-related lung pathology. B.T. Mossman. 2000;12(1-2):141-8. Review PubMed · Publisher

Abstract

For reasons that are unclear, poorly soluble particulates are associated with the development of inflammation, fibrogenesis, and carcinogenesis in the rat. The pathogenesis of these changes may be triggered by distinct or species-specific cellular responses to inhaled particulates in a manner similar to known fibrogenic and carcinogenic fibers, such as asbestos. Data reviewed here suggest that generation of oxidants by poorly soluble particulates is a key factor in the initiation of inflammation and generation of chemokines and cytokines in the rat. These substances then cause hyperplasia of epithelial cells and fibroblasts. The diminished or lack of proliferative responses by poorly soluble particulates in mice and primates, in comparison to rats, may be reflected by intrinsic differences in their oxidant-generating capacities or repair after oxidant injury or DNA damage.
Molecular Activation of Activator Protein-1 In Silica and Asbestos-Induced Carcinogenesis. V. Vallyathan, M. Ding, X. Shi, et al. 2000;12 Suppl 3:353-7. PubMed · Publisher

Abstract

Occupational exposures to asbestos and crystalline silica have been implicated in causing lung cancer and other pulmonary diseases in humans. Despite intensive research during the last decade on pulmonary carcinogenesis induced by these minerals, the exact molecular mechanisms involved in carcinogenesis are still unknown. Chronic inflammation and enhanced production of reactive oxygen species (ROS) generated by these particulates have been implicated in the development of tumors. In an attempt to understand the molecular basis of carcinogenesis induced by these particles, we investigated the potential activation of activator protein-1 (AP-1) by crocidolite and freshly fractured or aged crystalline silica in a JB6 P(+) cell line stably transfected with AP-1-luciferase reporter plasmid (in vitro) and in AP-1-luciferase reporter transgenic mice (in vivo). This transcription factor governs the expression of target genes that are involved in encoding cytokines, chemokines, growth factors, cell adhesion molecules, and acute-phase proteins that regulate inflammation, cell proliferation, and apoptosis. Results of our studies suggest that asbestos and silica activate AP-1 through generation of ROS. In in vitro studies, crocidolite asbestos caused a dose- and time-dependent AP-1 activation in JB6+ cells, which persisted for at least 72 h. In transgenic mice exposed to crocidolite asbestos, AP-1 activation increased significantly by 10-fold in lung tissue and 22-fold in bronchial tissue. This induction of AP-1 activation by crocidolite appears to be mediated through the influence of mitogen-activated protein kinase (MAPK) family members, specifically extracellular signal-regulating protein kinase, ERK 1, and ERK 2 (data not presented). Similarly, freshly fractured silica caused an 8-fold increase in AP-1 activation in JB6 P+cells and 22-fold increase in transgenic mice. The activation of AP-1 by freshly fractured silica was mediated through ERK1, ERK2, and p38 kinase. Activation of AP-1 by asbestos or silica was inhibited in both in vitro and in vivo systems by aspirin, which exhibits OH radical scavenging properties. It is proposed from these studies that asbestos and crystalline silica may promote carcinogenesis through specific mechanistic pathways stimulated by ROS.
Nuclear Factor Kappa-B Activation by Particles and Fibers. R.P. Schins, K. Donaldson. 2000;12 Suppl 3:317-26. PubMed · Publisher

Abstract

In recent years, particle research has focused on activation pathways of transcription factors that are known to regulate genes whose abnormal expression is associated with the pathogenesis of particle-associated lung disorders such as fibrosis, cancer, COPD, and asthma. This article reviews the effects of different particles and fibers on the transcriptional activation of nuclear factor kappa-B (NF-kB), which is involved in the activation of a variety of proinflammatory genes. Particulates that have been found to activate NF-κB, include asbestos, man-made fibers, quartz, and ambient particulates, such as residual oil fly ashes (ROFA) and diesel exhaust particles (DEP). In line with this, a number of NF-κB-regulated genes have been found to be upregulated, such as tumour necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), the interleukins IL-6 and IL-8, cyclooxygenase- II (COX-II), and inducible nitric oxide synthase (iNOS). Important mechanisms involved in the activation of NF-kB by particles or fibers include a role for reactive oxygen species, arachidonic acid metabolism, and particle- or fiber-specific physiochemical properties (e.g., transition metals, fiber dimensions) in processes such as lipid peroxidation and (frustrated) phagocytosis. Intracellularly, NF-κB may be activated via several pathways, for example, involving protein kinase C, tyrosine kinase, or calpain. Future research on NF-κB activation by particles or fibers should aim to further identify these and other pathways and to determine the in vivo significance of this activation in the pathogenesis of lung disease.
Occupational and Environmental Factors Enhancing the Genotoxicity of Asbestos. Q. Rahman, E. Dopp, M. Lohani, et al. 2000;12 Suppl 3:157-65. PubMed · Publisher

Abstract

Epidemiological and experimental studies have suggested the enhancement of asbestos-induced disease processes by simultaneous exposure to kerosene, its soot, and cigarette smoke in asbestos-exposed animals as well as in humans. To determine the influence of these factors on the genotoxic potential of asbestos, a micronucleus test was performed in Syrian hamster embryo fibroblasts (SHE) and human lymphocytes. To observe the specific chromosomal damages, multicolor fluorescence in situ hybridization (FISH) was done in the lymphocytes from smokers and nonsmokers exposed in vitro to asbestos. Significantly higher numbers of micronuclei were observed in SHE cells after combined treatment with chrysotile and kerosene soot (111 micronuclei/1000 cells) in comparison to chrysotile and kerosene soot separately. Kinetochore staining revealed mainly clastogenic effects in all the cases. In human lymphocytes exposed in cultures to chrysotile and crocidolite the numbers of micronuclei were found higher in smokers than nonsmokers. Multicolor FISH assay suggested that asbestos fibers inflict high damage within 1q12 and in the region between 1cen and 1q12 of chromosome 1. In the exposed population of an asbestos cement factory, the highest genetic damage was found in the blood lymphocytes of exposed smokers. The study suggests that smokers occupationally exposed to asbestos and domestically to kerosene soot are at higher risk for the early development of asbestos-induced diseases.
Oncogenes and Tumor Suppressor Genes in the Carcinogenicity of Fibers and Particles. A.B. Kane. 2000;12 Suppl 3:133-40. PubMed · Publisher

Abstract

Asbestos fibers and crystalline silica are carcinogenic to humans when inhaled into the lungs. Asbestos fibers and cigarette smoke most likely act as cofactors in the induction of lung cancer. Point mutations in the K-ras oncogene and the p53 tumor-suppressor gene are frequent in lung cancers and are consistent with the known mutagenic spectrum of tobacco-smoke carcinogens. The FHIT tumor suppressor gene is also frequently inactivated in lung cancers of smokers and in workers who were exposed to asbestos. Recent molecular studies of p53 tumor suppressor gene mutations and p53 protein expression in the lungs of patients with lung cancer and occupational exposure to crystalline silica and other dusts have been conducted. Mutations in the p53 gene were detected at a frequency similar to those in smoking-related lung cancers. Expression of p53 protein can be detected by immunohisto-chemistry in preneoplastic epithelial lesions in the lungs of smokers and workers. Human malignant mesotheliomas frequently show overexpression of p53 protein; however, point mutations at the p53 tumor suppressor gene or ras oncogene locus are rare. Most cases of malignant mesotheliomas have codeletions of the p15 and p16 tumor suppressor genes and alterations at the NF2 tumor suppressor gene locus with monosomy of chromosome 22. The molecular alterations characteristic of malignant mesotheliomas may develop during later stages of tumor progression and may not reflect the direct genotoxic effects of fibers on the target cell population.
Pathogenesis of Fibrosis Produced by Asbestos and Man-Made Mineral Fibers: What Makes a Fiber Fibrogenic?. A. Churg, J. Wright, B. Gilks, et al. 2000;12 Suppl 3:15-26. PubMed · Publisher

Abstract

Recent studies have revealed a wide array of molecular and cellular changes in cells and whole lungs exposed to asbestos fibers, changes that are presumed to be related to asbestos-induced fibrogenesis. These include generation of reactive oxygen species (ROS), induction of cell signaling factors and proinflammatory cytokines, and induction of fibrogenic mediators. Tumor necrosis factor-alpha (TNFα) appears to play a crucial role, since mice with TNFα receptor genes knocked out are resistant to asbestos-induced fibrosis. However, many man-made mineral fibers (MMVF) are able to generate ROS, cell signaling factors, and proinflammatory cytokines (probably every fiber causes expression of TNFα), but there is no clear correlation between the ability of MMVF to initiate these events and their ability to produce fibrosis. Moreover, asbestos produces fibrosis in tracheal explant systems without increasing TNFα expression, and nonfibrogenic dusts induce fibrogenic mediators such as transforming growth factor-beta (TCFβ) and platelet-derived growth factor (PDGF) but not procollagen in such systems. It remains uncertain whether alveolar macrophages are central to fibrosis, as is often assumed, or whether fibers penetrating tissue are the real effector agents. Fiber length, biopersistence, and dose clearly do play a very important role in fibrogenesis, since short fibers, readily degraded fibers, and small numbers of fibers of any type are nonfibrogenic. There is some evidence to suggest that short and nonpersistent fibers produce quantitatively less of the mediators just described, but the ability of macrophages to clear fibers is probably crucial to preventing fibrosis. Thus, molecular and cellular events must combine in as yet uncertain ways with abnormalities at a more "'macroscopic" level before fibrosis can become established.
Pathogenicity of a special-purpose glass microfiber (E glass) relative to another glass microfiber and amosite asbestos. R.T. Cullen, A. Searl, D. Buchanan, et al. 2000;12(10):959-77. PubMed · Publisher

Abstract

This article describes the activity of an E-glass microfiber (104E) during chronic inhalation and intraperitoneal injection studies in rats. Results are compared with another microfiber of similar dissolution rate (k(dis)), code 100/475, and the more durable amosite asbestos, both of which we had previously used in similar experiments (Davis et al., 1996). Rats were exposed to aerosol concentrations of 1000 fibers (longer than 5 microm)/ml, as measured by optical microscopy, for 7 h/day, 5 days/wk. Subgroups of rats were followed for mean lung burden, early and late signs of fibrosis, and tumor incidence. At the end of 12 mo of exposure, the mean number of 104E fibers of all lengths in the lungs was approximately double that for amosite but two-thirds of that for 100/475. For fibers longer than 15 microm, the mean 104E burden was similar to that for the amosite and more than twice that of the 100/475. After a 12-mo recovery period, the retained lung burdens (of fibers of all lengths) were approximately 30% of those at 12 mo for both microfibers, and somewhat higher (approximately 44%) for amosite. Amosite and 100/475 fibers longer than 15 microm were more persistent in the lungs than 104E fibers. The chemical composition of 104E fibers did not appear to have been significantly altered by up to 24 mo of residence in lung tissue, whereas the composition of 100/475 was substantially altered over the same time period. From the inhalation study, out of the pathology subgroup of 43 animals exposed to 104E microfibers, 10 had lung tumors (7 carcinoma, 3 adenoma) and 2 had mesotheliomas, whereas in 42 rats exposed to amosite asbestos, there were 16 lung tumors (7 carcinoma, 9 adenoma) and 2 mesotheliomas. The 104E- and amosite-treated animals had similar levels of fibrosis. In contrast, 38 animals treated with 100/475 had little fibrosis, 4 lung tumors (adenomas), and no mesotheliomas. The greater pathogenicity of the 104E fibers, compared to 100/475 fibers, might be partly explained by the greater numbers of long fibers retained in the lung after 12 mo of inhalation. However, we speculate that modification of surface properties by extensive selective leaching of some glass components reduces the toxic potential of 100/475. In a parallel intraperitoneal injection study, 104E caused considerably more mesotheliomas (21 rats out of 24) than 100/475 (8 rats out of 24). In addition, 104E appeared to be more active than amosite asbestos, since mesotheliomas appeared much more quickly in the 104E-treated animals. In conclusion, we have shown that two microfiber types, 100/475 and 104E, of similar dissolution rates, had markedly different pathogenicity in rats. We believe that this contrast is only partly due to differences in numbers of long fibers and that differences in surface properties of the fibers, possibly due to proportionately greater leaching of 100/475 fibers, play an important role.
Role of Iron in the Cellular Effects of Asbestos. E.A. Aust, L.G. Lund, C.C. Chao, et al. 2000;12 Suppl 3:75-80. PubMed · Publisher

Abstract

Research to understand how the physical characteristics of asbestos fibers impact the pathological effects has intensified in the past 10 years. The role that iron, intrinsic or acquired, may play has been the subject of many of these investigations. Asbestos catalyzes many of the same reactions that iron does, including lipid peroxidation and DNA damage. At physiological pH, mobilization of iron from the fibers by a low-molecular-weight chelator greatly enhances these reactions. Iron is also mobilized from asbestos fibers in human lung epithelial (A549) cells after the fibers are endocytized. The iron appears to move from a low-molecular-weight pool to nonferritin proteins and ferritin. The amount of iron in the low-molecular-weight pool was directly correlated with the toxicity of the asbestos. Glutathione (CSH) levels in these cells were dramatically reduced after asbestos treatment as a result of CSH efflux. This was not related to the iron associated with the fibers, but appeared to be due in some way to the silicate structure. The presence of the mobilized iron in the cells depleted of CSH creates a very oxidizing environment. Asbestos treatment of cells resulted in DNA oxidation, as assessed by formation of 8-hydroxy-2'-deoxyguanosine (8-oxo-dCJ. The DNA oxidation was dependent upon the iron associated with the fibers and the enzymatic generation of (•) NO by the cells. The induction of the inducible form of nitric oxide synthase (iNOS), responsible for the production of "NO, was dependent upon the presence of iron from the fibers and the decrease in CSH. One without the other did not lead to induction of iNOS. Asbestos was mutagenic in hgprt-gpt(+) V79 Chinese hamster lung cells. The mutagenicity was dependent upon iron, intrinsic or acquired. Addition of (•) NO synergistically increased the mutagenicity of the asbestos, suggesting that in cells that respond to asbestos by making (•) NO, the response will be enhanced. This also suggests that the responses will be enhanced in the presence of activated macrophages producing (•) NO or in the presence of cigarette smoke, because of the presence of (•) NO and iron chelators in the smoke.
Role of Mitogen-Activated Protein Kinases, Early Response Protooncogenes, and Activator Protein-1 in Cell Signaling by Asbestos. B. Mossman, A. Hubbard, A. Shukla, et al. 2000;12 Suppl 3:307-16. PubMed · Publisher

Abstract

Cell signaling by pathogenic minerals may initiate the transactivation of genes that are critical to carcinogenesis and fibroproliferative diseases of the lung and pleura. We have shown previously that stimulation of the mitogen-activated protein kinase (MAPK) cascade by asbestos fibers leads to phosphorylation events involved in transactivation of lun and Fos proteins that comprise the activator protein-1 (AP-1) transcription factor. Recently, we have also used AP-1 luciferase reporter transgenic mice and immunocytochemistry to show that transactivation of AP-1 occurs in bronchiolar and alveolar epithelial cells after inhalation of asbestos fibers. After inhalation of asbestos, epithelial cells of the lung also show increased immunoreactivity of pliosphorylated extracellular signal regulated kinases (ERKs 1/2) at sites of fibrogenesis. The availability of lung epithelial cell-specific promoters has allowed the creation of transgenic mice with mutations in the transactivation domains of key receptors and protein intermediates that comprise the MAPK signaling cascade. These rodent models may reveal whether cell signaling events initiated by mineral dusts in epithelial cells are critical to the development of cell proliferation, apoptosis, and lung disease.
Safety assessment of continuous glass filaments used in eclipse. J.E. Swauger, J.W. Foy. 2000;12(11):1071-84. PubMed · Publisher

Abstract

Eclipse is a cigarette that produces smoke by primarily heating, rather than burning, tobacco. The Eclipse heat source assembly employs a continuous filament glass mat jacket to insulate the heat source. The glass mat insulator is composed of continuous glass filaments and a binder. The purpose of this article is to address the potential toxicological significance of the continuous glass filaments under the conditions of intended use. Transfer data and the unique physical characteristics of the filaments demonstrate that significant exposure of the smoker will not occur. The available environmental survey data clearly demonstrate that Eclipse smokers are extremely unlikely to be exposed to continuous glass filaments at a level that represents a biologically significant increase over background exposure to glass fibers. The chemical composition of the continuous glass filaments used in Eclipse is generally similar to C-glass fiber compositions such as MMVF 11 that have failed to produce either tumors or fibrosis in chronic inhalation studies conducted in rats. In vitro dissolution data demonstrate that the continuous glass filaments used in Eclipse are more soluble than biologically active fibers such as rock wool (MMVF 21) or asbestos. However, the continuous glass filaments used in Eclipse were not as soluble in simulated extracellular lung fluid as representative C-glass fibers (MMVF 10 and MMVF 11). In brief, exposure of Eclipse smokers to continuous glass filaments is extremely unlikely to occur at a level that may be construed to be of biological significance.

1990s

Acute biological effects of intratracheally instilled titanium dioxide whiskers compared with nonfibrous titanium dioxide and amosite in rats. Y. Ishihara, H. Kyono, N. Kohyama, et al. 1999;11(2):131-49. PubMed · Publisher

Abstract

The dimensions of man-made mineral fiber whiskers are similar to those of some kinds of asbestos. Thus these mineral fibers raise the concern for potential health hazard for workers exposed in the occupational environments. This study was designed to define acute biological effects of intratracheally administered titanium dioxide whiskers (TO1) compared with nonfibrous titanium dioxide (TOP) and UICC amosite (Ams), and their relations to acute lung inflammation in rats. The observed geometric mean length (microm) and width (microm) and geometric standard deviation are: TO1(2.1[2.0], 0.14[1. 53]); Ams (4.3[3.3], 0.31[1.9]); and TOP (50 nm, 1-2 microm aggregates). Ten-week-old Wistar-Jcl male rats received a single tracheal injection of test materials at doses between 0.05 and 1.0 mg/rat. Control animals were injected with the same volume of saline. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected from rats on days 1, 3, and 7 after administration. In the group injected with TO1, total protein, cytokine-induced neutrophil chemoattractant (CINC)/growth-regulated gene product (GRO), interleukin (IL) 1beta, and tumor necrosis factor (TNF) alpha increased on day 1. Subsequently, total elastolytic activity and fucose levels in BAL increased by day 3. All parameters, except for fucose in BAL, recovered to the normal levels. Animals in the Ams group showed increased total protein and CINC/GRO and decreased total elastolytic activity in a dose-dependent manner on day 1. The fucose level increased on day 3 in the Ams group. All parameters returned to their control levels on day 7. Animals in the TOP group did not show significant changes any of parameters during the experimental period. Gene expression of TNF-alpha and monocyte chemoattractant protein (MCP) 3 in the lung increased dose-dependently in the animals treated with the three materials. The mRNAs for eotaxin and MIP-1alpha were overexpressed in the lung of animals treated with Ams and TO1, while RANTES mRNA was overexpressed dose-dependently in the lung of animals treated with Ams on day 1. Onset of inflammatory response was more rapid in the Ams group than the TO1 group. Recovery of the fucose level in BAL was slower in the TO1 group than in the Ams group, though we observed similar histopathological changes in the lung of animals with TO1 or Ams. We conclude that whisker-induced acute biological effects in the lung may be related to the shape of the whiskers and not to their chemical composition or surface crystal structure, showing biological effects similar to those of UICC amosite.
Models for mesothelioma incidence following exposure to fibers in terms of timing and duration of exposure and the biopersistence of the fibers. G. Berry. 1999;11(2):111-30. PubMed · Publisher

Abstract

The health effects of inhaled fibers are related to the intensity and duration of exposure and occur many years after the exposure. In particular, the incidence of mesothelioma after exposure to asbestos is proportional to the intensity of exposure (fibers per milliliter of air) and the duration of exposure, and to the time that has elapsed since the exposure. The incidence increases with time since exposure to a power of between 3 and 4. The disease process resulting from exposure to fibers in the air is presumably related to the dose of fibers in the lungs, which depends on the exposure level and duration, and also on the size characteristics of the fibers influencing their inhalation and retention in the lungs. Models incorporating these characteristics have been found to be satisfactory in explaining the incidence of mesothelioma over time after exposure to asbestos. Most of the epidemiological modeling has been for occupational exposure to one of the amphibole asbestos types (crocidolite or amosite), for which heavy exposure produces a high incidence of mesothelioma. Occupational exposure to chrysotile asbestos has resulted in a much lower incidence of mesothelioma. Crocidolite asbestos is much more biopersistent than chrysotile asbestos in the sense that after retention in the lungs it is eliminated only slowly (half-time of several years). If fibers are eliminated then the dose in the lungs declines following exposure, and this may influence the disease process. This concept is more important for synthetic mineral fibers, such as glass wool, which are used as a substitute for asbestos. These fibers are much less biopersistent than asbestos, with half-times of weeks or even days. Biopersistence is related to the dissolution of fibers. This is a physical-chemical process that may be expected to proceed at about the same rate in rats and humans. The predicted effect of biopersistence of fibers has been explored using the basic mesothelioma incidence model generalized to include a term representing exponential elimination over time. The influence of solubility of fibers on the mesothelioma rate is 17 times higher in humans than in rats. This is because rats are aging and developing cancer at a much quicker rate than humans, and hence the influence of dissolution is less. Thus, the predicted mesothelioma incidence in humans is highly dependent on the rate of elimination across the range covering asbestos and the more durable synthetic fibers, but in rats a similar dependence occurs at a 17 times higher rate of elimination corresponding to the less durable synthetic fibers. The possible carcinogenic effects of fibers are often determined from animal experiments, but these results suggest that the extrapolation from rats to humans is highly dependent on the biopersistence of fibers, in the situation where the elimination is through dissolution of fibers at a rate independent of species and the speed of the cancer process is species dependent. This implies that relatively soluble fibers that do not produce disease in rat experiments are even less likely to produce disease in humans.
Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster. Part I. Results of a subchronic study and dose selection for a chronic study. T.W. Hesterberg, C. Axten, E.E. McConnell, et al. 1999;11(9):747-84. PubMed · Publisher

Abstract

A multidose, subchronic inhalation study was used to estimate the maximum tolerated dose (MTD) of 901 fiberglass (MMVF10.1) for a chronic inhalation study using hamsters. Subchronic study results indicated that 30 mg/m(3) [250-300 WHO fibers (>5 microm long)/cm(3) and 100-130 fibers/cm(3) >20 microm long] meets or exceeds the estimated MTD, and chronic study results confirmed this. For the subchronic study, hamsters were exposed 6 h/day, 5 days/wk, for 13 wk to MMVF10.1 at 3, 16, 30, 45, and 60 mg/m(3) (36, 206, 316, 552, or 714 WHO fibers/cm(3)), then monitored for 10 wk. Results demonstrating MTD were: inflammatory response (all fiber exposures); elevated lung cell proliferation with @ges;16 mg/m(3); lung lavage neutrophil elevations with @ges;16 mg/m(3) and lactate dehydrogenase (LDH) and protein elevations with > or = 30 mg/m(3); and persistent abnormal macrophage/fiber clumps in lungs exposed to 45 and 60 mg/m(3), which suggest overloading of clearance mechanisms. For the chronic study, hamsters were exposed for 78 wk to MMVF10a (901 fiber glass) or MMVF33 (special-application 475 fiberglass) at approximately 300 WHO fibers/cm(3) ( approximately 100 fibers/cm(3) @gt;20 @mu;m long), or to amosite asbestos at an equivalent concentration and 2 lower concentrations. All fiber-exposed animals had pulmonary inflammation, elevated lung lavage cells, and increased lung cell proliferation. Between 52 and 78 wk of exposure, lung burdens of all fibers increased at an accelerated rate, suggesting impairment of clearance mechanisms. MMVF33 and amosite induced fibrosis and pleural mesothelioma. These findings substantiate that exposures in the chronic study adequately tested the toxic potential of fiberglass.
Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part II. Results of chronic exposure. E.E. McConnell, C. Axten, T.W. Hesterberg, et al. 1999;11(9):785-835. PubMed · Publisher

Abstract

Fiberglass (FG) is the largest category of man-made mineral fibers (MMVFs). Many types of FG are manufactured for specific uses building insulation, air handling, filtration, and sound absorption. In the United States, > 95% of FG produced is for building insulation. Several inhalation studies in rodents of FG building insulation have shown no indication of pulmonary fibrosis or carcinogenic activity. However, because of increasing use and potential for widespread human exposure, a chronic toxicity/carcinogenicity inhalation study of a typical building insulation FG (MMVF 10a) was conducted in hamsters, which were shown to be highly sensitive to the induction of mesotheliomas with another MMVF. A special-application FG (MMVF 33) and amosite asbestos were used for comparative purposes. Groups of 140 weanling male Syrian golden hamsters were exposed via nose-only inhalation for 6 h/day, 5 days/wk for 78 wk to either filtered air (chamber controls) or MMVF 10a, MMVF 33, or amosite asbestos at 250-300 WHO fibers/cm(3) with two additional amosite asbestos groups at 25 and 125 WHO fibers/cm(3). They were then held unexposed for 6 wk until approximately 10-20% survival. After 13, 26, 52, and 78 wk, various pulmonary parameters and lung fiber burdens were evaluated. Groups hamsters were removed from exposure at 13 and 52 wk and were held until 78 wk (recovery groups). Initial lung deposition of long fibers (>20 microm in length) after a single 6-h exposure was similar for all 3 fibers exposed to 250-300 fibers/cm(3). MMVF 10a lungs showed inflammation (which regressed in recovery hamsters) but no pulmonary or pleural fibrosis or neoplasms. MMVF 33 induced more severe inflammation and mild interstitial and pleural fibrosis by 26 wk that progressed in severity until 52 wk, after which it plateaued. While the inflammatory lesions regressed in the recovery animals, pulmonary or pleural fibrosis did not. A single multicentric mesothelioma was observed at 32 wk. No neoplasms were found in the remainder of the study. Amosite asbestos produced dose-related inflammation and pulmonary and pleural fibrosis as early as 13 wk in all 3 exposure levels. The lesions progressed during the course of the study, and at 78 wk severe pulmonary fibrosis with large areas of consolidation was observed in the highest 2 exposure groups. Progressive pleural fibrosis with mesothelial hypertrophy and hyperplasia was present in the thoracic wall and diaphragm in most animals and increased with time in the recovery hamsters. While no pulmonary neoplasms were observed in the amosite exposed hamsters, a large number of mesotheliomas were found; 25 fibers/cm(3), 3.6%; 125 fibers/cm(3), 25.9%; and 250 fibers/cm(3), 19.5%. For the 3 fiber types, the severity of the lung and pleural lesions generally paralleled the cumulative fiber burden, especially those >20 microm length, in the lung, thoracic wall, and diaphragm. They also inversely paralleled the in vitro dissolution rates; that is, the faster the dissolution, the lower were the cumulative lung burdens and the less severe the effects.
Studies on the chronic toxicity (inhalation) of four types of refractory ceramic fiber in male Fischer 344 rats. R.W. Mast, E.E. McConnell, R. Anderson, et al. 1995;7(4):425-67. PubMed · Publisher

Abstract

Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure, a chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Five groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 30 mg/m(3) (approximately 220 fibers/cm(3)) of three types [kaolin-based, high-purity, and aluminum zirconia silica (AZS)] of "size-selected" RCF fibers (approximately 1µ in diameter and approximately 20 um in length) and an "after-service" heat-treated (2400°F for 24 h) kaolin-based fiber for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and then sacrificed at 30 mo. A positive control group of 80 F344 rats was exposed to 10 mg/m(3) chrysotile asbestos. Croups of 3-6 animals were sacrificed at 3, 6, 9, 12, 15, 18, and 24 mo to follow the progression of lesions and to determine fiber lung burdens. Additional groups of 3 rats were removed from exposure at 3, 6, 9, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. Lung burdens increased rapidly for all RCFs, appearing to plateau by about 12 mo. By 24 mo, lung burdens ranged from 2.6 to 9.6 × 10(5) fiberslmg of dry lung tissue for the RCFs tested. Treatment-related lesions were restricted to the lungs. To some extent all types of RCF resulted in macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 3 mo of exposure. Interstitial fibrosis was observed at 6 mo for all types of RCF, except the "after-service" fiber where fibrosis was not seen until 12 mo. The lesions progressed in severity until 12-15 mo, after which they plateaued. A minimal amount of focal pleural fibrosis was first observed at 9 mo and progressed to a mild severity by the end of the study. Fxposure-related pulmonary neoplasms (bronchoalveolar adenomas and carcinomas combined) were observed with all 4 types of RCF [kaolin, 16 of 123 (13%); AZS, 9 of 121 (7.4%); high-purity, 19 of 121 (15.7%); and "after-service,"4 of 118 (3.4%)], compared to 2 of 120 (1.5%) in the untreated air controls. Pleural mesotheliomas were observed in two kaolin, three AZS, two high-purity, and one "after-service" exposed rats. A comparable but slightly greater amount of fibrosis was observed in the lungs of the positive (chrysotile asbestos) controls. The incidence of bronchoalveolar neoplasms in the chrysotile exposed rats was 13 of 69 (18.8%), and a mesothelioma occurred in 1 (1.4%) animal. The results of this study showed that the four types of RCF studied had carcinogenic activity in rats at the maximum tolerated dose.

Browse every journal in the library or the library by type of article, or return to medical research.

This page is provided for general informational purposes and does not constitute legal advice. Every asbestos case turns on its own facts, exposure history, diagnosis, deadlines, available evidence, and applicable law. Reviewing this page does not create an attorney-client relationship. For advice about your specific situation, call 833-4-ASBESTOS for a free case review.

Asbestos

Exposure

Look it up

By location

Cell types

Treatment & help

Cancers

Lung disease

Not sure

Trust claims

Lawsuits

Benefits

Guides & deadlines

Look up

History

Read & watch

The firm

Reach us