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1.
J Occup Health ; 63(1): e12282, 2021 Jan.
Article in English | MEDLINE | ID: mdl-34679210

ABSTRACT

OBJECTIVES: Asbestos causes lung cancer and malignant mesothelioma in humans, but the precise mechanism has not been well understood. MicroRNA (miRNA) is a short non-coding RNA that suppresses gene expression and participates in human diseases including cancer. In this study, we examined the expression levels of miRNA and potential target genes in lung tissues of asbestos-exposed mice by microarray analysis. METHODS: We intratracheally administered asbestos (chrysotile and crocidolite, 0.05 or 0.2 mg/instillation) to 6-week-old ICR male mice four times weekly. We extracted total RNA from lung tissues and performed microarray analysis for miRNA and gene expression. We also carried out real-time polymerase chain reaction (PCR), Western blotting, and immunohistochemistry to confirm the results of microarray analysis. RESULTS: Microarray analysis revealed that the expression levels of 14 miRNAs were significantly changed by chrysotile and/or crocidolite (>2-fold, P < .05). Especially, miR-21, an oncogenic miRNA, was significantly upregulated by both chrysotile and crocidolite. In database analysis, miR-21 was predicted to target tumor suppressor genes programmed cell death 4 (Pdcd4) and reversion-inducing-cysteine-rich protein with kazal motifs (Reck). Although real-time PCR showed that Pdcd4 was not significantly downregulated by asbestos exposure, Western blotting and immunohistochemistry revealed that PDCD4 expression was reduced especially by chrysotile. Reck was significantly downregulated by chrysotile in real-time PCR and immunohistochemistry. CONCLUSIONS: This is the first study demonstrating that miR-21 was upregulated and corresponding tumor suppressor genes were downregulated in lung tissues of asbestos-exposed animals. These molecular events are considered to be an early response to asbestos exposure and may contribute to pulmonary toxicity and carcinogenesis.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Asbestos, Crocidolite/administration & dosage , Asbestos, Serpentine/administration & dosage , GPI-Linked Proteins/genetics , Gene Expression/drug effects , MicroRNAs/genetics , RNA-Binding Proteins/genetics , Animals , Asbestos/toxicity , Disease Models, Animal , Down-Regulation , Lung/pathology , Male , Mice , Mice, Inbred ICR , Microarray Analysis , Up-Regulation
2.
Perm J ; 242020.
Article in English | MEDLINE | ID: mdl-32097115

ABSTRACT

INTRODUCTION: Asbestos-related diseases and cancers represent a major public health concern. OBJECTIVE: To conduct a systematic review and meta-analysis to demonstrate that asbestos exposure increases the risk of prostate cancer. METHODS: The PubMed, Cochrane Library, Embase, and ScienceDirect databases were searched using the keywords (prostate cancer OR prostatic neoplasm) AND (asbestos* OR crocidolite* OR chrysotile* OR amphibole* OR amosite*). To be included, articles needed to describe our primary outcome: Risk of prostate cancer after any asbestos exposure. RESULTS: We included 33 studies with 15,687 cases of prostate cancer among 723,566 individuals. Asbestos exposure increased the risk of prostate cancer (effect size = 1.10, 95% confidence interval [CI] = 1.05-1.15). When we considered mode of absorption, respiratory inhalation increased the risk of prostate cancer (1.10, 95% CI = 1.05-1.14). Both environmental and occupational exposure increased the risk of prostate cancer (1.25, 95% CI = 1.01-1.48; and 1.07, 1.04-1.10, respectively). For type of fibers, the amosite group had an increased risk of prostate cancer (1.12, 95% CI = 1.05-1.19), and there were no significant results for the chrysotile/crocidolite group. The risk was higher in Europe (1.12, 95% CI = 1.05-1.19), without significant results in other continents. DISCUSSION: Asbestos exposure seems to increase prostate cancer risk. The main mechanism of absorption was respiratory. Both environmental and occupational asbestos exposure were linked to increased risk of prostate cancer. CONCLUSION: Patients who were exposed to asbestos should possibly be encouraged to complete more frequent prostate cancer screening.


Subject(s)
Asbestos/adverse effects , Environmental Exposure/statistics & numerical data , Prostatic Neoplasms/epidemiology , Asbestos/administration & dosage , Asbestos, Amphibole/administration & dosage , Asbestos, Amphibole/adverse effects , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/adverse effects , Humans , Incidence , Inhalation Exposure , Male , Occupational Exposure/statistics & numerical data , Prostate-Specific Antigen , Ronidazole
3.
Basic Clin Pharmacol Toxicol ; 126(4): 374-388, 2020 Apr.
Article in English | MEDLINE | ID: mdl-31628893

ABSTRACT

Asbestos (Mg-hydrosilicate; chrysotile) is known to cause pleural diseases, pulmonary fibrosis and lung cancers, via mechanisms strongly depending on diameter-length ratio and possibly metal content. A critical question is whether synthetic hydrosilicate nanotubes (NTs) of short length possess little toxic potential compared to chrysotile. Five Mg- and two NiNTs of different lengths were assessed for cytotoxicity and pro-inflammatory responses in THP-1 macrophages and human bronchial epithelial lung cells (HBEC3-KT), in comparison with chrysotile. NT lengths/diameters were characterized by TEM, surface areas by BET- and BJH analysis, and chemical composition by XRD. The different Mg- and NiNTs induced little cytotoxicity in both cell models, in contrast to chrysotile that induced marked cytotoxicity. The two longest synthetic MgNTs, with median lengths of 3 and 5 µm, induced increased levels of pro-inflammatory cytokines in THP-1 macrophages, but much less than chrysotile (median length 15 µm) and silica nanoparticles (Si10). The shortest NTs did not induce any increase in cytokines. In HBEC3-KT cells, all synthetic NTs induced no or only small changes in cytokine responses, in contrast to chrysotile and Si10. The synthetic NTs induced lower TGF-ß responses than chrysotile in both cell models. In conclusion, the pro-inflammatory responses were associated with the length of synthetic hydrosilicate NTs in THP-1 macrophages, but not in HBEC3-KT cells. Notably, the shortest NTs showed no or little pro-inflammatory activity or cytotoxicity in both cell models. Such a safety by design approach is important for development of new materials being candidates for various new products.


Subject(s)
Asbestos, Serpentine/toxicity , Inflammation/chemically induced , Lung/pathology , Nanotubes , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/chemistry , Bronchi/cytology , Bronchi/pathology , Cell Line , Cells, Cultured , Cytokines/metabolism , Epithelial Cells/cytology , Epithelial Cells/pathology , Humans , Inflammation/pathology , Lung/cytology , Macrophages/pathology , Nanoparticles , Silicon Dioxide/administration & dosage , Silicon Dioxide/toxicity
4.
Toxicol Appl Pharmacol ; 351: 74-92, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29705295

ABSTRACT

This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6 h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length > 20 µm/cm3: Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm3: Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm3 in the brake-dust was similar to that in the chrysotile (Brake-dust 710-1065; Chrysotile 532-1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score < 1.7) or changes in bronchoalveolar lavage (BAL) indices from the air control. Chrysotile BAL indices did not differ from the air control. Pathologically, there was low level of inflammation and epithelial hyperplasia, but no fibrosis (Wagner score ≤ 3). Crocidolite induced elevated neutrophils and cell damage (BAL), persistent inflammation, microgranulomas, and fibrosis (Wagner scores 4) which persisted through the post exposure period. Confocal microscopy of snap-frozen chestwalls showed no difference between control, brake-dust and chrysotile-HD groups or in thickness of visceral or parietal pleural. The crocidolite exposure resulted in extensive inflammatory response, collagen development and adhesions between the visceral and parietal surfaces with double the surface thickness. These results provide essential information for the design of a subsequent subchronic study.


Subject(s)
Asbestos, Crocidolite/toxicity , Asbestos, Serpentine/toxicity , Dust , Inhalation Exposure/adverse effects , Lung/drug effects , Pleura/drug effects , Animals , Asbestos, Crocidolite/administration & dosage , Asbestos, Serpentine/administration & dosage , Dose-Response Relationship, Drug , Particle Size , Rats , Time Factors
5.
Arch Toxicol ; 92(5): 1785-1795, 2018 05.
Article in English | MEDLINE | ID: mdl-29523930

ABSTRACT

Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 ÷ 5.0 µg/cm2, 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (≥ 10%) between the asbestos dose at 5 µg/cm2 and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = - 1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target.


Subject(s)
Asbestos/toxicity , DNA Methylation/drug effects , Transcriptome/drug effects , Antigens, Neoplasm/genetics , Asbestos/chemistry , Asbestos, Crocidolite/administration & dosage , Asbestos, Crocidolite/toxicity , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/toxicity , Carbonic Anhydrase IX/genetics , Cell Line , Dose-Response Relationship, Drug , Epithelial Cells/drug effects , Humans , Lung Neoplasms/chemically induced , Lung Neoplasms/genetics , Mesothelioma/chemically induced , Mesothelioma/genetics , Mesothelioma, Malignant , Real-Time Polymerase Chain Reaction
6.
Environ Sci Pollut Res Int ; 25(23): 22378-22388, 2018 Aug.
Article in English | MEDLINE | ID: mdl-28905283

ABSTRACT

Chrysotile is the most widely used form of asbestos worldwide. China is the world's largest consumer and second largest producer of chrysotile. The carcinogenicity of chrysotile has been extensively documented, and accumulative evidence has shown that chrysotile is capable of causing lung cancer and other forms of cancer. However, molecular mechanisms underlying the tumorigenic effects of chrysotile remained poorly understood. To explore the carcinogenicity of chrysotile, Wistar rats were administered by intratracheal instillation (by an artificial route of administration) for 0, 0.5, 2, or 8 mg/ml of natural chrysotile (from Mangnai, Qinghai, China) dissolved in saline, repeated once a month for 6 months (a repeated high-dose exposure which may have little bearing on the effects following human exposure). The lung tissues were analyzed for viscera coefficients and histopathological alterations. Expression of P53, P16, C-JUN, and C-FOS was measured by western blotting and qRT-PCR. Our results found that chrysotile exposure leads the body weight to grow slowly and lung viscera coefficients to increase in a dose-dependent manner. General sample showed white nodules, punctiform asbestos spots, and irregular atrophy; moreover, HE staining revealed inflammatory infiltration, damage of alveolar structures, agglomerations, and pulmonary fibrosis. In addition, chrysotile can induce inactivation of the anti-oncogene P53 and P16 and activation of the proto-oncogenes C-JUN and C-FOS both in the messenger RNA and protein level. In conclusion, chrysotile induced an imbalanced expression of cancer-related genes in rats' lung tissue. These results contribute to our understanding of the carcinogenic mechanism of chrysotile.


Subject(s)
Asbestos, Serpentine/toxicity , Cyclin-Dependent Kinase Inhibitor p16/genetics , Lung/drug effects , Proto-Oncogene Proteins c-fos/genetics , Tumor Suppressor Protein p53/genetics , Animals , Asbestos, Serpentine/administration & dosage , Blotting, Western , China , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Regulation/drug effects , Genes, Tumor Suppressor , Lung/physiology , Male , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Rats, Wistar , Tumor Suppressor Protein p53/metabolism
7.
Environ Sci Pollut Res Int ; 25(23): 22328-22333, 2018 Aug.
Article in English | MEDLINE | ID: mdl-28685333

ABSTRACT

According to global estimates, at least 107,000 people die each year from asbestos-related lung cancer, mesothelioma, and asbestosis resulting from occupational exposure. Chrysotile accounts for approximately 90% of asbestos used worldwide. Artificial substitutes can also be cytotoxic to the same degree as chrysotile. But only a few researchers focused on their genetic effects and mutagenicity information which is useful in evaluating the carcinogenicity of chemicals. In this study, chrysotile from Mangnai, Qinghai, China, and an artificial substitute, rock wool fiber were prepared as suspensions and were tested at concentrations of 50, 100, and 200 µg/ml in V79 lung fibroblasts. Chromosome aberrations were detected by micronucleus assay after exposure for 24 h, and DNA damage were estimated by single cell gel electrophoresis after exposure for 12, 24, or 48 h. According to the results, chrysotile and rock wool fibers caused micronuclei to form in a dose-dependent manner in V79 cells; olive tail moment values increased in a dose- and time-dependent manner. When V79 cells were exposed to a concentration of 200 µg/ml, the degree of DNA damage induced by chrysotile fibers was greater than rock wool fibers. Our study suggests that both chrysotile and rock wool fibers could induce chromosome aberrations and DNA damage. These materials are worthy of further study.


Subject(s)
Asbestos, Serpentine/toxicity , Chromosome Aberrations/drug effects , DNA Damage/drug effects , Lung/cytology , Mineral Fibers/toxicity , Animals , Asbestos, Serpentine/administration & dosage , Cell Line , China , Cricetulus , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Fibroblasts/physiology , Lung/drug effects , Micronucleus Tests , Mutagens/toxicity , Single-Cell Analysis/methods
8.
J Immunotoxicol ; 13(3): 335-48, 2016 05.
Article in English | MEDLINE | ID: mdl-26484633

ABSTRACT

Calcined Serpentine (CS) is used in various formulations of alternative systems of medicine as a tonic to vital organs and as an anti-inflammatory agent. The process of calcination or incineration is believed to render non-toxic, gently absorbable, adaptable and digestible properties to the mineral compounds. The present study characterized CS and also evaluated its immunostimulatory potential. CS was characterized by using transmission electron microscopy (TEM), X-ray powder diffraction, atomic absorption spectroscopy and CHNS analysis. The characterized CS was further evaluated for its immunomodulatory potential in Swiss mice. X-Ray diffraction analysis revealed that the CS contained silicates of magnesium, calcium and iron as major minerals. Elemental composition and heavy metal analyses showed a presence of various inorganic elements/heavy metals, albeit at levels well below daily permissive intake values. TEM analysis of the test CS revealed a presence of nano particles with an average size of 10-20 nm (≈ 26% of total material). Oral administration of CS to mice at 50, 75, 100 or 200 µg/kg body weight for 10 days led to enhanced levels of total IgG, IgG1, IgG2a and IgG2b in ovalbumin-immunized mice as well as ex vivo lymphocyte proliferation and levels of TH1 (IL-2, IFNγ) and TH2 (IL-4, IL-10) cytokines produced by their cultured splenocytes. Similarly, CS treatment resulted in enhanced delayed-type hypersensitivity responses in GRBC-primed hosts. CS also activated host peritoneal macrophages, as indicated by increases in phagocytic activity and in TLR-2, CD80 and CD86 expression. The CS did not affect liver, kidney and spleen histology. Taken together, the results indicated that absorbed CS was stimulatory of host cell-mediated immune responses. It is hypothesized for now that the immunomodulatory effect of CS may have been due, in part, to a presence of nanoparticles on the CS; further study is required to validate this viewpoint.


Subject(s)
Asbestos, Serpentine/immunology , Macrophages, Peritoneal/immunology , Silicates/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Administration, Oral , Animals , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/chemistry , Cell Proliferation , Cells, Cultured , Complementary Therapies , Cytokines/metabolism , Hot Temperature , Humans , Hypersensitivity, Delayed , Immunity, Humoral , Immunization , Mice , Microscopy, Electron, Transmission , Nanoparticles/chemistry , Silicates/chemistry , X-Ray Diffraction
9.
Asian Pac J Allergy Immunol ; 33(1): 59-64, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25840635

ABSTRACT

OBJECTIVE: To assess three plasma adipokines that might act as biomarkers useful in determining persons exposed to asbestos. METHOD: Sixty subjects were included in the study, 30 male workers from factories manufacturing cement products using chrysotile asbestos, and 30 volunteer controls comprising 15 men and 15 women. Fasting venous blood specimens were submitted for blood chemistry examination and analysis of plasma levels of three adipokines, i.e. adipsin, adiponectin and resistin. RESULTS: (1) Compared with non-obese subjects, the adiponectin levels were lower in obese subjects, resistin levels were higher, and hemoglobin concentrations were lower. (2) Adipsin levels in the workers were significantly higher than in the controls (p < 0.005), and this difference was not related to body fat. (3) There were no statistically significant differences in adiponectin, resistin, and adipsin levels between the male and female controls. (4) Adiponectin in the male controls was significantly higher than that in the male workers (p <0.05). (5) Female controls had significantly higher percentages of body fat (p < 0.0005) and resistin (p < 0.02) levels than male controls and male workers. (6) A significant negative correlation existed between resistin and hemoglobin levels levels (r= -0.336, p < 0.01). (7) Overall adipsin levels among male workers were significantly higher than among control subjects (p < 0.005); the six workers in whom asbestos bodies (AB) were detected did not have significantly higher levels of adipsin than those of workers without AB having been detected. CONCLUSIONS: Although the findings apparently showed higher adipsin levels in the workers, its value as a biomarker for asbestos exposure requires confirmation from studies on a larger group of subjects.


Subject(s)
Adiponectin/blood , Asbestos, Serpentine , Inhalation Exposure , Occupational Exposure , Resistin/blood , Adiponectin/genetics , Adipose Tissue/metabolism , Adult , Aged , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/blood , Biomarkers/blood , Case-Control Studies , Complement Factor D/genetics , Complement Factor D/metabolism , Female , Gene Expression , Humans , Male , Middle Aged , Resistin/genetics , Thailand
10.
J Toxicol Sci ; 39(2): 363-70, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24646718

ABSTRACT

Possible teratogenicity of 3 different asbestos (crocidolite, chrysotile and amosite) was assessed in CD1(ICR) mice. Dams on day 9 of gestation were given a single intraperitoneal administration at dose of 40 mg/kg body weight of asbestos suspended in 2% sodium carboxymethyl cellulose solution in phosphate buffered saline, while dams in the control group were given vehicle (10 ml/kg body weight). Dams and fetuses were examined on day 18 of gestation. To compare with the control group, the mean percentage of live fetuses in implantations in the group given crocidolite and the incidence of dams with early dead fetuses in the groups given chrysotile or amosite were increased. While no external or skeletal malformation was observed in the control group, the incidence of external malformation (mainly reduction deformity of limb) in the group given amosite, and the incidences of skeletal malformation (mainly fusion of vertebrae) in the all dosed groups were significantly increased. The result indicated that asbestos (crocidolite, chrysotile and amosite) have fetotoxicity and teratogenicity in mice.


Subject(s)
Asbestos, Amosite/toxicity , Asbestos, Crocidolite/toxicity , Asbestos, Serpentine/toxicity , Fetus/abnormalities , Fetus/drug effects , Limb Deformities, Congenital/chemically induced , Musculoskeletal Abnormalities/chemically induced , Teratogenesis/drug effects , Abnormalities, Multiple , Animals , Asbestos, Amosite/administration & dosage , Asbestos, Crocidolite/administration & dosage , Asbestos, Serpentine/administration & dosage , Female , Gestational Age , Incidence , Injections, Intraperitoneal , Limb Deformities, Congenital/epidemiology , Maternal-Fetal Exchange , Mice , Mice, Inbred ICR , Musculoskeletal Abnormalities/epidemiology , Pregnancy , Specific Pathogen-Free Organisms
11.
Inhal Toxicol ; 22(11): 937-62, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20695727

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.


Subject(s)
Asbestos, Amosite/administration & dosage , Asbestos, Serpentine/administration & dosage , Inhalation Exposure/adverse effects , Lung/pathology , Particulate Matter/administration & dosage , Pleura/pathology , Animals , Asbestos, Amosite/metabolism , Asbestos, Amosite/toxicity , Asbestos, Serpentine/metabolism , Asbestos, Serpentine/toxicity , Lung/drug effects , Lung/metabolism , Male , Particulate Matter/toxicity , Pilot Projects , Pleura/drug effects , Pleura/metabolism , Rats , Time Factors
12.
Arch Environ Occup Health ; 63(2): 71-5, 2008.
Article in English | MEDLINE | ID: mdl-18628078

ABSTRACT

The authors designed this study to show the effects of orally ingested asbestos on the lungs and pleura. They designated 3 groups of rats: group A (n = 18) was given 1.5 g/L asbestos in water, group B (n = 18) was given 3 g/L asbestos in water, and group C (n = 15), as a control group, was given only water. Histopathological evaluation of lungs and pleura of the rats after 6 months revealed significant mesothelial proliferation and asbestos bodies. After 9 months, more rats exhibited mesothelial proliferation in group B than in group A (p < .05). The number of rats with asbestos bodies in their lungs was greater in group B than in group A. More rats in group B than in group A had asbestos in their spleen. The authors observed mesothelial proliferation in all group B rats at the end of 12 months. Ingested asbestos traveled from the gastrointestinal system to the lungs, likely via a lymphohematological route, leading to mesothelial proliferation, which may lead to malignancies.


Subject(s)
Asbestos, Serpentine/toxicity , Lung/drug effects , Pleura/drug effects , Administration, Oral , Animals , Asbestos, Serpentine/administration & dosage , Lung/physiopathology , Mesothelioma/chemically induced , Pleura/physiopathology , Rats , Rats, Wistar , Turkey
13.
Inhal Toxicol ; 20(1): 63-73, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18236224

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).


Subject(s)
Asbestos/administration & dosage , Inhalation Exposure , Lung/drug effects , Lung/pathology , Animals , Asbestos/adverse effects , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/adverse effects , Inhalation Exposure/adverse effects , Macaca fascicularis , Male , Particle Size , Time
14.
Inhal Toxicol ; 19(4): 317-23, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17365036

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.


Subject(s)
Asbestos, Serpentine/toxicity , Gene Expression Regulation, Enzymologic/physiology , Heme Oxygenase-1/biosynthesis , Heme Oxygenase-1/genetics , Lung/enzymology , Lung/pathology , Animals , Asbestos, Serpentine/administration & dosage , Cells, Cultured , Gene Expression Regulation, Enzymologic/drug effects , Humans , Male , Rats , Rats, Wistar , Time Factors
15.
Inhal Toxicol ; 18(5): 313-32, 2006 May.
Article in English | MEDLINE | ID: mdl-16513591

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.


Subject(s)
Asbestos, Serpentine/toxicity , Inhalation Exposure , Lung/drug effects , Aerosols , Animals , Asbestos, Amphibole/toxicity , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/metabolism , Body Burden , Bronchoalveolar Lavage Fluid/cytology , Cell Proliferation/drug effects , L-Lactate Dehydrogenase/metabolism , Lung/metabolism , Lung/pathology , Male , Metabolic Clearance Rate , Microscopy, Confocal , Rats , Rats, Wistar
16.
Inhal Toxicol ; 15(14): 1387-419, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14648356

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.


Subject(s)
Asbestos, Amphibole/pharmacokinetics , Asbestos, Amphibole/toxicity , Asbestos, Serpentine/pharmacokinetics , Asbestos, Serpentine/toxicity , Inhalation Exposure , Lung/pathology , Aerosols , Animals , Asbestos, Amphibole/administration & dosage , Asbestos, Serpentine/administration & dosage , Male , Mineral Fibers , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , Rats
17.
Regul Toxicol Pharmacol ; 38(1): 58-70, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12878055

ABSTRACT

The use in the past, and to a lesser extent today, of chrysotile asbestos in automobile brake systems causes health concerns among professional mechanics. Therefore, we conducted four separate tests in order to evaluate an auto mechanic's exposure to airborne asbestos fibers while performing routine brake maintenance. Four nearly identical automobiles from 1960s having four wheel drum brakes were used. Each automobile was fitted with new replacement asbestos-containing brake shoes and then driven over a predetermined public road course for about 2253 km. Then, each car was separately brought into a repair facility; the brakes removed and replaced with new asbestos-containing shoes. The test conditions, methods, and tools were as commonly used during the 1960s. The mechanic was experienced in brake maintenance, having worked in the automobile repair profession beginning in the 1960s. Effects of three independent variables, e.g., filing, sanding, and arc grinding of the replacement brake shoe elements, were tested. Personal and area air samples were collected and analyzed for the presence of fibers, asbestos fibers, total dust, and respirable dust. The results indicated a presence in the air of only chrysotile asbestos and an absence of other types of asbestos. Airborne chrysotile fiber exposures for each test remained below currently applicable limit of 0.1 fiber/ml (eight-hour time-weighted average).


Subject(s)
Air Pollutants, Occupational/analysis , Asbestos, Serpentine/analysis , Automobiles , Air Pollutants, Occupational/adverse effects , Asbestos, Serpentine/administration & dosage , Asbestos, Serpentine/adverse effects , Environmental Monitoring/methods , Humans , Inhalation Exposure , Occupational Health , Particle Size , Threshold Limit Values
18.
Regul Toxicol Pharmacol ; 38(1): 71-7, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12878056

ABSTRACT

Data exist that show that chrysotile asbestos does not retain its mineral properties, or biological activity, at temperatures far below the olivine transformation point. Temperatures hundreds of degrees below this point cause the mineral to lose structural water with accompanying crystal structure degradation. The loss of structure is accompanied by modification of its surface and reduction or loss of biological activity. Using heating studies and milling as an approximation of thermal and mechanical shear stress that chrysotile is subjected to on a brake lining, biological blunting is shown to begin much earlier than the olivine transformation process. Minimal degradation of the chrysotile surface structure imparts a disproportionately great effect on its biological activity. Biological and epidemiological data for brake workers exposed to chrysotile asbestos should be viewed in context with the conditions of service to which the product was subjected over a lower range of temperatures than previously considered important.


Subject(s)
Air Pollutants, Occupational/adverse effects , Asbestos, Serpentine/adverse effects , Automobiles , Asbestos, Serpentine/administration & dosage , Crystallization , Environmental Monitoring/methods , Humans , Inhalation Exposure , Occupational Exposure , Occupational Health , Particle Size , Surface Properties
19.
Am J Respir Cell Mol Biol ; 28(1): 51-60, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12495932

ABSTRACT

Nitration of proteins by peroxynitrite (ONOO-) has been shown to critically alter protein function in vitro. We have shown previously that asbestos inhalation induced nitrotyrosine formation, a marker of ONOO- production, in the rat lung. To determine whether asbestos-induced protein nitration may affect mitogen-activated protein kinase (MAPK) signaling pathways, lung lysates from crocidolite and chrysotile asbestos-exposed rats and from sham-exposed rats were immunoprecipitated with anti-nitrotyrosine antibody, and captured proteins were subjected to Western blotting with anti-phospho-extracellular signal-regulated kinase (ERK)1/2 antibodies. Both types of asbestos inhalation induced significantly greater phosphorylation of ERK1/2 in rat lung lysates than was noted after sham exposure. Phosphorylated ERK proteins co-immunoprecipitated with nitrotyrosine. Moreover, in MAPK functional assays using Elk-1 substrate, immunoprecipitated phospho-ERK1/2 in lung lysates from both crocidolite-exposed and chrysotile-exposed rats demonstrated significantly greater phosphorylation of Elk-1 than was noted after sham exposure. Asbestos inhalation also induced ERK phosphorylation in bronchoalveolar lavage cells. Lung sections from rats exposed to crocidolite or chrysotile (but not from sham-exposed rats nor from rats exposed to "inert" carbonyl iron particles) demonstrated strong immunoreactivity for nitrotyrosine and phospho-ERK1/2 in alveolar macrophages and bronchiolar epithelium. These findings suggest that asbestos fibers may activate the ERK signaling pathway by generating ONOO- or other nitrating species that induce tyrosine nitration and phosphorylation of critical signaling molecules.


Subject(s)
Asbestos, Crocidolite/pharmacology , Asbestos, Serpentine/pharmacology , Lung/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinases/metabolism , Nitrates/metabolism , Tyrosine/metabolism , Animals , Asbestos, Crocidolite/administration & dosage , Asbestos, Serpentine/administration & dosage , Enzyme Activation , Immunohistochemistry , Inhalation Exposure , Lung/enzymology , Male , Mitogen-Activated Protein Kinase 3 , Phosphorylation , Precipitin Tests , Rats , Rats, Inbred F344
20.
Int J Mol Med ; 8(1): 43-7, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11408947

ABSTRACT

We examined karyotypic changes of tumorigenic human bronchial epithelial cell lines transformed by asbestos fibers. Using Calyculin A mediated premature chromosome condensation (PCC) assay and Giemsa-trypsin banding, we showed that the common changes of all tumorigenic cell lines were the loss of one or two copies of chromosome 5, the monosomy of chromosome 19 and the increased trisomy of chromosome 8. The results indicate that the karyotypic change of chromosome 5, 8 and 19 could play an important role in asbestos-induced tumorigenic conversion of human bronchial epithelial cells from an immortalized to tumorigenic state.


Subject(s)
Asbestos, Serpentine/administration & dosage , Bronchi/drug effects , Cell Transformation, Neoplastic/genetics , Karyotyping/methods , Animals , Bronchi/cytology , Bronchi/metabolism , Cell Line , Cell Line, Transformed , Cell Transformation, Neoplastic/drug effects , Chromosome Aberrations , Chromosomes, Human, Pair 19/drug effects , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 5/drug effects , Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 8/drug effects , Chromosomes, Human, Pair 8/genetics , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Mice , Mice, Nude , Mitotic Index
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