Determinants of the pathogenicity of man-made vitreous fibers (MMVF)

Introduction and objectives: A number of man-made vitreous fibers (MMVF) have been developed over the years to replace asbestos fibres in its uses as insulating material. Concerns have been raised that these man-made fibers may also pose a significant health hazard when inhaled during their manufacture and application. As will be discussed in this brief overview, dose, dimension and durability of fibrous particles are key parameters with respect to the induction of adverse pulmonary effects, including carcinogenicity as well as non-cancer effects. In particular, fiber biopersistence plays a most important role for pulmonary pathogenicities, and consequently biopersistence receives greatest attention in the search of new fibrous materials. Methods and results: Tests to evaluate fiber biopersistence include the administration of fibers by a short-term inhalation (5 days) or intratracheal instillation into rats. Advantages of the inhalation methodology include the even distribution throughout the lung administered by a physiological process. A disadvantage of this method is the limited respirability of long fibers in the rat whereas they are well respirable by humans. Such long fibers (>20 7m) have the greatest potential for tumorigenicity and need special consideration in connection with the evaluation of fiber biopersistence. Enrichment of the inhaled aerosol by these long fibers needs to be considered in order to deposit enough of them in the lower respiratory tract of the rat. In contrast, the advantage of the instillation technique is that these long fibers can be delivered to the lung. However, the major disadvantages of intratracheal instillations are the potential of the administered fibers to form clumps and aggregates in the airways and the induction of a major inflammatory response when high-bolus doses are administered. This could influence fiber dissolution in the lungs significantly. Conclusions: At the same delivered lung dose, a fiber of low biopersistency has the least effect and is, therefore, less likely to induce lung or pleural tumors even under chronic exposure conditions. Respective animal studies with more fibers of different biopersistence have confirmed this general principle. It is very important that, when evaluating and interpreting fiber effects observed in experimental animals, species differences with respect to respirability, lung retention and mechanisms of responses are considered.     

Respiratory disease caused by MMVF fibers and yarn]

The non-carcinogenic effects of vitreous fibres on the human respiratory apparatus have been the subjects of numerous studies on large exposed populations. No evidence seems to have been produced of the existence of a fibrogenic effect. However, no definite and agreed opinion has yet been expressed by the main Agencies and Institutions working in the field of prevention. As a contribution to the discussion, the paper presents the experience of the Clinica del Lavoro of Milano involving 1000 subjects who underwent broncho-alveolar lavage during assessment and checking for suspected occupational respiratory disease. A group of 23 cases was selected who were exposed to vitreous fibres without other significant exposures to factors considered hazardous for the respiratory apparatus, especially asbestos. We observed 7 cases of alveolitis; 6 cases with pleural thickening; 2 cases of interstitial disease. On the basis of the nature of exposure (duration, latency from beginning and from the end of hazardous occupation), of the data obtained from the examination of the bronchial lavage liquid (presence of vitreous fibres, siderocytes, cellularity), and of the clinical and laboratory data (X-ray, PFR), the view expressed is tendentially reassuring concerning the possible effects of vitreous fibres on the respiratory apparatus. Although the existence of an irritative type of lesion that manifests in the form of alveolitis and localised pleural thickening seems possible, albeit in a limited number of cases, it does however appear much more difficult to admit the existence of a fibrogenic effect.     

Influence of airspace geometry and surfactant on the retention of man-made vitreous fibers (MMVF 10a)

Inhaled and deposited man-made vitreous fibers (MMVF) 10a (low-fluorine preparation of Schuller 901 insulation glass) were studied by electron microscopy in hamster lungs, fixed by intravascular perfusion within 23 +/- 2 min (SD) of the initial inhalation. We found fibers on the surfaces of conducting airways and alveoli. In the airways, 89% of the fibers were totally and 11% partially covered by lining-layer material. In the alveoli, 32% of the fibers were totally submersed; others touched the alveolar wall, stuck at one end, bridging the airspace. Studies in a surface balance showed that fibers were immersed into the aqueous subphase by approximately 50% at film surface tensions of 20-25 mJ/m2) and were submersed (totally immersed; i.e., totally surrounded by fluid) at approximately 10 mJ/m2). Fibers were also found to be phagocytosed by macrophages. We found a substantial number of particle profiles within alveolar blood capillaries. Fiber length and alveolar geometry appear to be important limiting factors for the submersion of vitreous fibers into the lungs' surface lining layer.     

人造矿物纤维对细胞DNA损伤作用的体外研究

目的比较研究１０种人造矿物纤维（ＭＭＭＦ）对人肺泡上皮细胞（Ａ５４９细胞）ＤＮＡ的损伤及修复作用。方法选用日本纤维状物质研究协会提供的１０种标准人造矿物纤维（ＪＦＭ）,用单细胞凝胶电泳法,以Ａ５４９细胞作为靶细胞,测定了细胞ＤＮＡ链断裂、损伤后修复及ＤＮＡＤＮＡ链间交联。结果１０种ＪＦＭ纤维都可引起不同程度的ＤＮＡ链断裂、ＤＮＡＤＮＡ链间交联及抑制ＤＮＡ损伤后的修复功能。综合分析发现：微细玻璃纤维的遗传毒性最强,硅灰石的遗传毒性最低。它们的作用程度均低于温石棉。结论ＪＦＭ纤维均具有一定程度的体外遗传毒性,但均低于ＵＩＣＣ温石棉Ｂ。     

Evaluation of exposure to man-made vitreous fibers by nasal lavage

The objectives of this study were to develop a biomonitoring method for the assessment of exposure to man-made vitreous fibers (MMVF), to examine the level of exposure to MMVF in the prefabricated house industry, and to study nasal inflammatory reactions and respiratory symptoms associated with MMVF among workers. Nasal lavage was performed on workers from two factories, and concentrations of MMVF were measured by electron microscopy. Cytokines (IL-6, IL-8, TNF-alpha, and IFN-gamma) were also assayed and inflammatory cells (lymphocytes, eosinophils, neutrophils, and macrophages) were counted microscopically. Concentrations of airborne fibers (longer than 5 microm) were measured for comparison. Moreover, the exposure to MMVF and the related symptoms were studied with a structured questionnaire. In nasal lavage samples, the mean concentration of MMVF (length >1.5 microm) was 3260 f/ mL in Factory 1, 1680 f/mL in Factory 2, and below 500 f/mL in the control group. About 52% of the retained fibers were longer than 100 microm. The group-specific mean concentrations of MMVF in nasal lavage samples correlated with production rates and airborne fiber levels in both plants. The airborne concentrations of MMVF both in the breathing zone and fixed-point samples were low (below 0.1 f/cm(3)). No significant differences in the biological response (inflammatory cells, cytokines) were found between the groups exposed and the control group. The workers complained of some irritation of the skin, eyes, and upper respiratory tract, which could be reduced by appropriate protective equipment. It is concluded that nasal lavage can be used as a biomonitoring method in the assessment of MMVF exposure.     

Characterization of current exposure to man-made vitreous fibres (MMVF) in the prefabricated house industry in Sweden

The exposure to man-made vitreous fibres (MMVF) was investigated at 11 Swedish plants manufacturing prefabricated wooden houses. Current fibre levels were studied by monitoring personal exposure using the membrane filter technique. All samples were analysed by phase contrast optical microscopy (PCOM) according to Swedish standard rules; they were also analysed using a set of modified criteria for fibre counting, developed for this study, which in addition also required straight, parallel and/or convergent edges of the fibres. The objective of this alternating counting method, the modified fibre method, was to exclude fibres with appearance other than MMVF, that might be present in the wood industries. The method was validated by scanning electron microscopy (SEM). In all, 120 samples were taken and 273 analyses were performed. The mean exposure (GM), analysed by the standard method, was for insulators 0.10 f ml⁻¹ (range 0.03–0.30 f ml⁻¹) and for woodcutters 0.09 f ml⁻¹ (range 0.05–0.19 f ml⁻¹). Analysed by the modified fibre method the insuslators were exposed to 0.029 f ml⁻¹ (range 0.013–0.077 f ml⁻¹) and the cutters to 0.021 f ml⁻¹ (range 0.014–0.033 f ml⁻¹). A significant difference was observed between the exposure for near-field workers/job titles and far-field workers/job titles. Analysis of fibre levels by the modified fibre method indicated that only a minor proportion, around 25%, of the total airborne fibres were MMVFs. The reliability of the alternative modified counting method was high, and a high correlation (r = 0.94) with the SEM results was also achieved.     

Current man-made mineral fibers (MMMF) exposures among ontario construction workers

Current occupational exposures to man-made mineral fibers (MMMF), including refractory ceramic fibers (RCF), were measured as part of an exposure assessment program for an epidemiological study pertaining to cancer and mortality patterns of Ontario construction workers. The assessments were carried out at commercial and residential sites. A total of 130 MMMF samples (104 personal and 26 area) was collected and included 21 RCF (16 personal and 5 area). The samples were analyzed by the World Health Organization method in which both respirable and nonrespirable airborne fibers are counted. The results show that Ontario construction workers' full-shift exposure to MMMF (excluding RCF) is generally lower than the American Conference of Governmental Industrial Hygienists' (ACGIH) recommended threshold limit value-time-weighted average (TLV-TWA) of 1 fibers/cc and thus should not present any significant hazard. However, approximately 40% of the occupational exposures to RCF are higher than ACGIH's TLV-TWA of 0.2 fibers/cc and present a significant potential hazard. Workers generally wore adequate approved respiratory protection, especially while performing particularly dusty tasks such as blowing, spraying, and cutting, so the actual exposure received by workers was lower than the reported values. Adequate control measures such as ventilation and respiratory protection should always be used when work involves RCF.     

人造矿物纤维诱导人支气管上皮细胞系恶性转化的研究

目的 比较温石棉、难溶性陶瓷纤维(RCF)、玻璃棉(GW)、岩棉(RW)对人支气管上皮细胞BEAS-2B细胞株的细胞毒性与致恶性转化的能力.方法 检测温石棉、RCF、GW、RW对BEAS-2B的细胞毒性;BEAS-2B细胞每10 d染毒24 h,共染毒6次,待细胞出现生长抑制后,用锚着不依赖性生长实验判断细胞恶性转化.结果 温石棉、RCF、GW、RW均对BEAS-2B细胞具有细胞毒性,并呈剂量一反应关系.染毒6次后,温石棉组、RCF组细胞生长速度加快,排列紊乱,失去接触抑制,出现复叠层生长,并可在软琼脂上生长,细胞集落形成率分别为4.6%和7.2%,与阴性对照组比较,差异有统计学意义(P<0.05);而GW组和RW组细胞集落形成率分别为0.6%和0.4%,与阴性对照组比较,差异无统计学意义(P>0.05).结论 温石棉组、RCF具有使BEAS-2B细胞发生恶性转化的能力,GW、RW染毒60 d未能使BEAS-2B细胞发生恶性转化.     

Size distributions of airborne superfine man-made mineral fibers determined by transmission electron microscopy

A survey was conducted to determine the size distribution of airborne man-made mineral fibers in three factories using bulk materials which contain many fibers with diameters less than 0.3 micrometers. Personal samples were taken in two of the factories visited. In all the cases a full length and diameter distribution, determined by transmission electron microscopy, are presented. Median diameters ranged from 0.1 to 0.3 micrometers and, as a result, a substantial proportion of the fibers would not be detected using light microscopy or scanning electron microscopy even for fibers longer than 5 micrometers.     

Lung cancer and exposure to man-made vitreous fibers: results from a pooled case-control study in Germany

BACKGROUND: To investigate the association between lung cancer and occupational exposure to man-made vitreous fibers (MMVF), a pooled analysis of two case-control studies was conducted in the years 1988-1994. METHODS: The case series consisted of 3498 males who were histologically or cytologically verified primary lung cancer cases. 3541 male population controls were drawn at random from the general population and matched to cases by sex, age, and place of residence. To examine the relationship between MMVF and lung cancer we asked all study subjects who worked for at least 6 months as construction and installation workers whether they ever installed or removed insulations and what kind of insulation material they used. RESULTS: Some 304 (8.7%) cases and 170 (4.8%) controls reported to have insulated with glass wool or mineral wool mats. Coded as ever/never exposed, the odds ratio was 1.48 (95% CI: 1.17-1.88), adjusted for smoking and asbestos. To be sure to exclude any confounding effect of asbestos, we tried to identify those cases and controls who insulated with glass wool or mineral wool mats only and never reported any asbestos exposure. For this group we calculated an odds ratio of 1.56 (95% CI: 0.92-2.65), after adjustment for smoking. An elevated risk was also estimated on the basis of an expert rating which was done for a subgroup of cases and controls. Ever exposure to MMVF (but not to asbestos) in this subgroup yielded an odds ratio of 1.30 (95% CI: 0.82-2.07). CONCLUSIONS: Our study provides some indication for an excess risk of man-made vitreous fibers. This result also persists after adjustment for smoking and asbestos.     

Biological effects of man-made mineral fibers (II)--their genetic damages examined by in vitro assay.

In order to study and compare genetic damage induced by 10 kinds of man-made mineral fibers (JFM fibers) in cells, human lung epithelial cells (A549) were exposed to JFM fibers and chrysotile for 1 h, then single-cell gel electrophoresis (SCGE) assay was used to detect DNA strand breaks, DNA-DNA interstrand crosslink and the ability of DNA to repair; The results showed that all 10 JFM fibers could induce DNA strand breaks, DNA-DNA interstrand crosslinks and inhibit the ability of DNA repair. When human embryo lung (HEL) cells were exposed to JFM fibers and chrysotile for 24 h respectively, the chromosomal aberration was analyzed and the results showed that chrysotile and most of JFM fibers at 5.0 micrograms/ml induced structural chromosomal aberration, but all of these effects were lower than that of chrysotile and were different among them, suggesting that 10 types of JFM fibers had genotoxicity with different degree in vitro, but all of them were lower than that of chrysotile.     

Laryngeal and hypopharyngeal cancer and occupational exposure to asbestos and man-made vitreous fibers: results of a case-control study

BACKGROUND: The data from a case-control study performed in France between 1989 and 1991 were used to test whether exposure to either asbestos or to man-made vitreous fibers (MMVF) is a risk factor for cancer of the larynx or the hypopharynx. METHODS: This study involved 315 incident cases of laryngeal cancer, 206 cases of hypopharyngeal cancer, and 305 hospital-based controls with other types of cancer, all recruited in 15 hospitals in six French cities. The subjects' past occupational exposure to asbestos and to four types of MMVF (mineral wool, refractory ceramic fibers, glass filaments, and microfibers) was evaluated based on their job history, with the aid of a job-exposure matrix. Odds ratios were calculated with unconditional logistic regression, with adjustment for smoking and drinking levels. RESULTS: Exposure to asbestos resulted in a significant increase in the risk of hypopharyngeal cancer (OR = 1.80, 95% CI: 1.08-2.99) and a nonsignificant increase in the risk of laryngeal cancer (OR = 1.24, 95% CI: 0.83-1.90). Risk was highest for the epilarynx (highest cumulative level of exposure: OR = 2.22, 95% CI: 1.05-4.71). Exposure to mineral wools was of borderline significance for the risk of hypopharyngeal cancer (OR = 1.55, 95% CI: 0.99-2.41), and nonsignificantly associated with the risk of laryngeal cancer (OR-1.33, 95% CI: 0.91-1.95). The risk was again highest for the epilarynx (OR = 1.85, 95% CI: 1.08-3.17). No significant results were observed for the other MMVF. CONCLUSIONS: These results suggest that asbestos exposure increases the risk of epilaryngeal and hypopharyngeal cancers. It is difficult to reach a conclusion about the effects of mineral wools, because nearly all the exposed subjects were also exposed to asbestos. The possible effects of other MMVF were difficult to assess in this study, because of the paucity of exposed subjects.     

Solubility of asbestos and man-made mineral fibers in vitro and in vivo: its significance in lung disease

Work on the solubility of asbestiform minerals and of man-made mineral fibers, both in vitro and in vivo, is reviewed. The significance of solubility in determining the pathogenic potential of these materials is also discussed.     

Asbestos and man-made vitreous fibers as risk factors for diffuse malignant mesothelioma: results from a German hospital-based case-control study

BACKGROUND: This study examines the role of occupational factors in the development of diffuse malignant mesothelioma with special emphasis on the dose-response relationship for asbestos and on the exposure to man-made vitreous fibers (MMVFs). METHODS: One hundred and twenty-five male cases, diagnosed by a panel of pathologists, were personally interviewed concerning their occupational and smoking history. The same number of population controls (matched for sex, age and region of residence) underwent similar interviews by trained interviewers. Odds ratios (OR) were calculated for an expert-based exposure index using conditional logistic regression. RESULTS: Exposure to asbestos shows the expected sharp gradient with an OR of about 45 for a cumulative exposure > 1.5 fiber years (arithmetic mean 16 fiber years). A significant OR was calculated even for the lowest exposure category "> 0 - < or = 0.15 fiber years". Although the mean cumulative exposure to MMVF is roughly 10% of the exposure to asbestos, an increased OR is observed in an ever/never evaluation. This observation is heavily hampered by methodical problems. A corresponding case-control study was performed using a lung tissue fiber analysis in addition to interviews. Both interviews and the lung tissue analysis yielded similar OR levels between the reference and the maximum exposure intervals. CONCLUSIONS: Despite a possible influence as a result of selection and information bias, our results confirm the previously reported observation of a distinct dose-response relationship even at levels of cumulative exposure below 1 fiber year. Moreover, the study confirms that asbestos is a relevant confounder for MMVF. A causal relationship between exposure to MMVF and mesothelioma could neither be detected nor excluded, as in other studies.     

Effect of size of man-made and natural mineral fibers on chemiluminescent response in human monocyte-derived macrophages.

Fiber size is an important factor in the tumorigenicity of various mineral fibers and asbestos fibers in animal experiments. We examined the time course of the ability to induce lucigenin-dependent chemiluminescence (CL) from human monocyte-derived macrophages exposed to Japan Fibrous Material standard reference samples (glass wool, rock wool, micro glass fiber, two types of refractory ceramic fiber, refractory mullite fiber, potassium titanium whisker, silicon carbide whisker, titanium oxide whisker, and wollastonite). We determined how fiber length or width might modify the response of cells. We found that the patterns of time-dependent increase of CL (sigmoid type) were similar for each sample except wollastonite. We observed a strong correlation between geometric-mean length and ability to induce CL in seven samples > 6 microm in length over the time course (largest r(2) = 0.9760). Although we also observed a close positive correlation between geometric-mean width and the ability to induce CL in eight samples < 1.8 microm in width at 15 min (r(2) = 0.8760), a sample of 2.4 microm in width had a low ability to induce CL. Moreover, the relationship between width and the rate of increase in ability to induce CL had a negative correlation at 30-60 min (largest r(2) = 0.7473). Our findings suggest that the release of superoxide from macrophages occurs nonspecifically for various types of mineral fibers depending on fiber length.     

Biological effects of man-made mineral fibers (I)--Reactive oxygen species production and calcium homeostasis in alveolar macrophages

10 types of standard mineral fiber samples (JFM fibers) were tested for their cytotoxicity in alveolar macrophages (AM) in vitro experiments, in which UICC chrysotile B was used as a positive control. The cytotoxicity included the production of superoxide anion radical and hydrogen peroxide, depletion of glutathione (GSH) and increase of intracellular free calcium. The results showed that chrysotile and most of the 10 mineral fibers could increase the production of superoxide anion and hydrogen peroxide, deplete the concentration of GSH and increase the level of free intracellular Ca2+ in AM. But all the effects of JFM fibers were lower than that induced by UICC chrysotile B. Although the cytotoxicity of JFM fibers were lower than that of asbestos, these mineral fibers should be used with highly care for workers in industries.     

Oxidative damage on DNA induced by asbestos and man-made fibers in vitro

Summary We compared the potential of asbestos and man-made fibers to attack DNA by the determination of the yield of 8-hydroxy-2-deoxyguanosine (8-OH-dGuo) under several in vitro conditions. Asbestos induced 6.6–99.8 of 8-OH-dGuo per 10⁵ dGuo in calf thymus DNA after 20 h of incubation, while the levels of 8-OH-dGuo in man-made fibers were low (3.6–9.4). The amounts of 8-OH-dGuo were strongly stimulated by the addition of H₂O₂ in asbestos, but not in man-made fibers. However, the yield of 8-OH-dGuo was induced more than that with asbestos by the further addition of FeSO₄ in attapulgite, fiberglass, potassium titanate whisker, and metaphosphate polymer. The addition of ethylene diamine tetraacetic acid (EDTA) promoted the induction of 8-OH-dGuo with asbestos and H₂O₂. The effects of mannitol (known as a hydroxy radical scavenger) were not dramatic on 8-OH-dGuo induction by all fibers except fiberglass and basic magnesium sulfate whisker, which induced higher amounts after mannitol addition than in these fibers and H₂O₂. Therefore, it was suggested that asbestos could damage DNA, resulting in 8-OH-dGuo as a cause of point mutation, and also several types of manmade fibers had similar effects to asbestos under certain conditions.     

A trial on the quantitative risk assessment of man-made mineral fibers by the rat intraperitoneal administration assay using the JFM standard fibrous samples

We tried to evaluate the carcinogenic risk of man-made mineral fiber based on the mesothelioma incidence in female F344 rats after intraperitoneal administration. Rats (female F344/ Nslc, 5-week-old, n=330) were observed for 2 years after the intraperitoneal administration of 5 to 20 mg of 9 types of the JFM (Japan Fibrous Material Research Association) standard fiber samples (glass wool, rock wool, micro fiber glass, three types of refractory fiber, potassium titanate whisker, silicon carbide whisker, titanium oxide whisker), wollastonite (natural fiber) and UICC chrysotile B. All rats administered 10 mg of silicon carbide whisker had developed peritoneal mesothelioma within a year. The cumulative incidence of peritoneal mesothelioma at the end of the experiment was 85% for 10 mg UICC chrysotile B, 77% for 10 mg of potassium titanate whisker, 70% for 5 mg of silicon carbide whisker, 20% for 5 mg of potassium titanate whisker, 20% for 20 mg of refractory fiber 2 and 10% for 20 mg of refractory fiber 1. Carcinogenicity was estimated 2.4 times for silicon carbide whisker and 0.23 for potassium titanate whisker in comparison with UICC chrysotile B. It has been well documented from several experimental studies that man-made fibers are safer than asbestos because of the different durability in the lung. Present results consistently suggest that man-made fibers with high durability have similar or higher risk as carcinogen than asbestos.     

人造钻石加工生产中发生不明原因中毒的调查分析

20 0 3年 9月 9日 ,新疆维吾尔自治区疾病预防控制中心接到新疆自治区某行政管理局的报告 ,反映其下属某单位在引进的人造钻石加工的生产中发生不明原因的头痛、头晕、腹泻、腹痛、水肿等症状 ,情况较为严重。接报后 ,自治区疾病预防控制中心前后派出三批相关人员赴现场进行样品检测、健康检查和流行病学调查 ,并采取了相应的预防干预措施 ,现将调查分析结果报告如下。1　现场卫生学调查该单位于 2 0 0 3年 4月引进了一条投资少、见效快的人造钻石加工生产线。该生产线为合作企业 ,由该单位出人员 (劳动力 )和场地 ,合作方出资金、设备和技…