Fibers are long particles whose length is several times more than their diameter. The capability of a fiber to cause lung pathology is especially conditioned by the “3 Ds”: dimension, dosage and durability. As for dimension, inhalable fibers (meaning those that are able to reach the pulmonary parenchyma) are considered to be those having a diameter smaller than 3μm, a length greater than 5μm and a length/diameter ratio equal to or greater than 3. It is accepted that thicker fibers, although they could be inhaled, are usually retained in the upper respiratory tract, and the shorter ones could be phagocyted by the alveolar macrophages and eliminated. Dosage refers to the quantity of fibers that reach the pulmonary parenchyma and can cause pathology when their concentration surpasses the capability of the defense mechanisms to eliminate them. Durability, or biopersistence, is the time that a fiber can remain in the lungs. It is determined by the rate at which the fiber can be dissolved or broken down once deposited, which is related to its chemical composition. These 3 characteristics of fibers condition their capacity to reach, remain in and accumulate in the lungs,1 resulting in lung pathology.

There are various types of fibers that can be classified in several ways.2–4 We propose for this review a classification according to origin and nature, shown in Table 1. First of all, the fibers are identified as either natural (as they are found in nature) or man-made (fabricated by humans). Both groups, natural and man-made, can be divided into organic or inorganic fibers. Organic natural fibers can be of animal (wool) or vegetable (cotton) origin. Within the inorganic natural fibers, there is a wide variety, and from this group asbestos stands out due to its ability to cause disease. Organic man-made fibers are those created by man using organic material. Within this group are artificial fibers, in which the raw material is natural but the process for obtaining the fiber is manufactured, like cellulose polymers, or synthetic, in which both the raw material and the process for obtaining the fiber are human fabrications, such as in the case of acrylic fibers or nylon.

Table 1.

General Fiber Classification.

Inorganic man-made fibers, produced by humans using inorganic material, can have a vitreous or crystalline structure. These are the most important man-made fibers due to the volume of their manufacturing and consumption, and they are generally known as man-made mineral fibers (MMMF). The most common MMMF have a vitreous structure (amorphous), and therefore MMMF are also generically known as synthetic vitreous fibers.

MMMF have some similarities with asbestos fibers, including the same aerodynamic properties. Nevertheless, while asbestos fibers generally tend to break up longitudinally, leading to long fibers that become thinner and thinner and can remain in the lungs over time, MMMF divide transversally, producing shorter and shorter segments that can be eliminated more effectively through the phagocytic system. In spite of these differences, due to the fact that there is so much information about the relationship between the inhalation of asbestos and the development of pleuropulmonary pathology, for years there have also been studies evaluating the possible toxicity of MMMF in the lungs and pleura. Furthermore, starting 2 decades ago, we now have the capability to manipulate matter on a nanoscale, leading to the appearance of nanoparticles, some of which have a fiber structure. The possibility that nanofibers could penetrate in the organism by inhalation and cause respiratory pathology has likewise awakened concern, and in recent years there have also been studies assessing their pathogenicity.

The objective of this review is to analyze the knowledge that exists today about MMMF and respiratory disease while updating a previous review that was published by this journal in 1996.5 First of all, the different types of MMMF are described, and then there is comment on studies in animals and in humans with each type. Since, as we have mentioned, the most common MMMF are vitreous and the studies in the literature have centered on these, in this review we will not deal with other MMMF types, and when we refer to “MMMF”, we refer to this type alone. Afterwards, and due to growing interest, we will specifically discuss nanofibers and the possibility of their causing respiratory pathology. The last part of this review provides the recommendations of national and international organisms for the use of MMMF and nanofibers.

MMMF are produced by melting raw material and giving it the desired shape by cooling it quickly. The most commonly used raw material is composed of silicates and varying quantities of inorganic oxides.

MMMF are typically classified into 3 types: continuous filament glass, mineral wool and refractory ceramic fibers (RCF).

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  Continuous filament glass fibers are more or less rectilinear, with uniform diameters, and are typically thicker than mineral wool fibers. As they become fragmented, the fibers break up into shorter fibers, but due to their thickness (between 3.5 and 25.0μm), they are not considered inhalable. They began to be manufactured at the beginning of the 20th century and they are basically used to reinforce materials used in insulation, electronics and construction industries.

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  Mineral wools are masses of interlocking, disorganized fibers with variable lengths and diameters, some of which may be inhalable. Mineral wools are classically divided into 3 types: fiberglass, stone wool and slag wool. Stone and slag wools were the first to be manufactured in the mid-nineteenth century, with a peak production in the mid-twentieth century, when glass wool (fiberglass insulation) gained in importance. They are basically used for thermal and acoustic insulation, typically in buildings, vehicles and appliances, as well as for inflammable materials and flame-retardant protection.

  Fiberglass microfibers, which are glass wool fibers with a diameter smaller than 1μm, merit special attention. They are used in high-tech products, as high-efficiency air filters, or in aerospace insulation.

  Since 1990, a new family of mineral wools has been developed, known as high-temperature insulation wool, which is made of alkaline-earth silicates. They are less biopersistent than RCF, have similar physical properties and can substitute these in some applications.

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  Refractory ceramic fibers are a mix of aluminum, silica and other refractory oxides. Their fibers have a diameter of 1.2–3.5μm, and their longitude is variable. They began to be commercialized between 1950 and 1960, and they are relatively new compared with other MMMF. They have several possible applications, but they are basically used as thermal insulation for high-temperature requirements, mainly at the industrial level.

Animal studies that evaluate the potential effects of MMMF on the respiratory tract have been done in rodents, particularly rats and hamsters. The latter are currently considered either imperfect or even inadequate for evaluating the toxicity of fibers in humans due to their lung architecture and ultrastructure, the excessive sensitivity of their pleura and the difficulty for developing lung cancer when exposed to mineral dust and biopersistent fibers.1 The types of administration used have been intrapleural, intraperitoneal, inhalation and intratracheal instillation. There is a debate about the suitability of using the intrapleural and intraperitoneal pathway for evaluating the carcinogenic risk of inhaled fibers, since these methods of administration are different from the standard entry and circumvents the natural defense mechanisms of the organism. Intracavitary instillation studies of different types of MMMF have often shown tumor induction, mostly mesotheliomas.6,7 In fact, it has been observed that, at sufficient doses, all mineral fibers can cause carcinogenesis.8 However, the high pathogenicity seen in this administration type has not been demonstrated in epidemiologic studies in persons or in animals with inhaled administration. For these reasons, today it is largely considered that the results of long-term, well-designed studies with inhaled administration are the best for predicting the effects on human health.9 As for the mentioned studies with inhaled administration, they initially presented important limitations due to the technology of the era, such as the use of short fibers. Towards the end of the 1980s, a new generation of these studies, initiated by the Research and Consulting Company (RCC) with a much greater control over all working conditions, provided much more reliable results. Below, we comment on the most significant of these, according to MMMF type.

Although in vitro studies are not considered appropriate for evaluating the toxicity of fibers,1 the International Agency for Research on Cancer (IARC)31 considered in 2006 that, overall, this type of studies are useful for discriminating between primary and secondary genotoxicity. They also may help detect potential adverse effects of new fibers and identify their mechanisms of action. For example, studies in cell cultures have shown that fiber toxicity is directly related with their length, as well as the fact that MMMF induce neoplastic transformation32,33 and genetic damage.34,35

Nanoparticles are defined as particles with a dimension of 100 nanometers or less. There is an ample diversity of nanoparticles derived from inorganic non-metallic elements such as carbon, silica or boron; inorganic metallic elements such as gold, silver or other metals; and organic or biological elements such as liposomes or virus. Using inorganic non-metallic elements, nanotubes are constituted, and although they are made of diverse materials, usually the term “nanotubes” is used for those made of carbon, as they are the most widely developed and used due to their physical and chemical characteristics. Carbon nanotubes (CNT) have great electrical conductivity and mechanical resistance (they are considered the most resistant fiber that can currently be manufactured) and are enormously stable thermally. These unique characteristics make them very useful for several applications, among these electronics, industrial engineering and medicine, among other fields. Structurally, CNT can be described as graphite sheets that are rolled into cylinders with one or more layers of thickness. They go from one to several nanometers wide and several micros in length, and this width/length ratio make them structurally similar to other fibers, like asbestos. The possibility that the inhalation of CNT could cause pathology similar to what is caused by asbestos has raised concern, and in recent years its pathogenicity has been researched.

In 2002, the IARC considered that there was not sufficient evidence of the carcinogenicity in humans of continuous fiberglass filament, mineral wools and RCF.4 Nonetheless, it underlined that the epidemiological studies had limitations that should be taken into consideration when interpreting the results, like the possibility of a poor assessment of the quantity of exposure to fibers, the difficulty to assess the risks of the workers exposed to the more durable fibers, the difficulty to adjust for confounding factors like smoking or exposure to asbestos, or the limitation of most workers being exposed to low levels of fibers. It was also emphasized that there were no data about the repercussions of MMMF exposure in workers who do not manufacture but instead use these fibers or work in their removal (e.g. in construction), and who may experience exposures that are occasionally higher, although on a more intermittent basis. For the IARC, however, in animal experimentation there is enough evidence for a specific group of fiberglass (such as E and 475), as well as RCF, to be considered carcinogenic. For fiberglass insulation, stone wool, slag wool and some more biopersistent fibers, like H fiber, the evidence of carcinogenicity in animal experimentation is limited, while for continuous fiberglass filament and for less biopersistent fibers there is not sufficient evidence. Thus, the IARC classifies fiberglass like E and 475, as well as RCF, as possible carcinogens in humans (group 2B); meanwhile, continuous fiberglass filament and glass, stone and slag wool are considered non-classifiable with regard to their carcinogenicity in humans (group 3).

In Spain, the National Institute for Occupational Safety and Hygiene (in Spanish, INSHT) has published guidelines for the determination of asbestos fibers and other fibers in the air using phase contrast microscopy.88 Since 2000, the guidelines incorporate the permissible exposure limit (PEL) for fibers other than asbestos in the list of limits for occupational exposure of chemical agents.89 For RCF and special-use fibers, the limit for occupational exposure is set at 0.5fiber/cm3, and for fiberglass and mineral wool, 1fiber/cm3. Although the exposure to MMMF during its production, use and elimination is believed to have been higher in the past, current mean exposure levels are generally less than 0.5inhalable fibers/cm3 (500000inhalable fibers/m3) in an average of 8 work hours. Higher levels have been measured, however, in the production of special-use fiberglass and RCF, and in the installation and removal of certain insulations. The concentrations of MMMF in the indoor and outdoor air in non-work settings are much lower.90–92 In addition to controlling PEL for the protection of workers, there are also recommendations about safety in the use of MMMF, such as those published by the International Labour Organization.93

With regards to nanofibers, conventional systems for detecting fibers, such as those used for asbestos or MMMF, have not been demonstrated to be practical and there is no international consensus about techniques for measuring nanoparticles in the workplace. Furthermore, we currently do not know the levels at which these nanofibers have adverse health effects, and there are therefore no specific exposure limits. For small-scale production situations, a simplified method has been developed for the qualitative assessment of risk of exposure to nanoparticles that allow decisions to be made about the necessary preventive measures.94 INSHT has also published technical reports with recommendations for the control of exposure to nanoparticles, using this simplified methodology.95,96

Although in experimental studies in rodents the intraperitoneal administration of high concentrations of mineral wools has caused the development of mesotheliomas, several studies with inhaled administration have not confirmed the appearance of neoplasms. Epidemiological studies in workers exposed to continuous fiberglass filament and mineral wool have also not been able to provide consistent evidence of association between the exposure to these fibers and risk for lung cancer or mesothelioma. One exception is about more biopersistent glass fibers, like E and 475, which have demonstrated in studies of intrapleural and inhaled administration the development of mesotheliomas and, in the case of E, lung cancer. For these reasons, continuous fiberglass filament and mineral wools are considered to have a non-classifiable carcinogenicity in humans, while more biopersistent fiberglass, like E and 475, are considered possible carcinogens.

As for the development of pulmonary fibrosis, animal experimentation studies using inhalation of glass wool have not confirmed its appearance, although minimal fibrosis was seen when stone wool was used. Isolated cases of lung fibrosis have been reported in workers exposed to fiberglass, and there have been reported cases of granulomatous disease similar to sarcoidosis in workers exposed to different mineral wools.

Regarding RCF, the information in the literature is more confusing. Experimentation studies have shown the induction of mesotheliomas after intraperitoneal administration, as well as fibrosis and tumors after the inhalation of high concentrations of RCF, but the interpretation of the results is difficult due to the lung overload phenomenon. Epidemiological studies have observed the appearance of pleural plaques in exposed worker, but no other type of diseases, such as interstitial fibrosis, lung cancer or mesothelioma, has been detected. Nevertheless, the results of epidemiologic studies with RCF are considered limited, and given the fact that asbestos induces pleural plaques and also pleural mesothelioma, there is concern about the possibility of RCF causing this type of tumor. For these reasons, RCF are currently considered possible carcinogens for humans. In recent years, programs have been developed that control exposure to RCF, but situations may arise with exposure to high concentrations that are less controlled, such as in demolition, where proper respiratory protection and adequate worker follow-up are both necessary.

In mice, CNT have been demonstrated to cause inflammatory, immune, fibrogenic and granulomatous responses according to the quantity of nanofibers and the administration pathway. It seems that inhaled CNT do not cause lung fibrosis, unlike when using intratracheal or pharyngeal administration, although they do cause pleural fibrosis. Several studies have evaluated the possibility that CNT could induce mesotheliomas, and only in 2 has there been evidence of this possibility, although only after the administration of characteristically long CNT (one with intraperitoneal and the other with scrotal administration). More studies are therefore needed in order to assess the risk of CNT for developing fibrosis and lung neoplasms. Until the biological and carcinogenic properties of nanoparticles are completely determined, measures should be taken to adequately control the exposure to these fiber nanomaterials, especially those that are longer and biopersistent.

The authors declare having no conflict of interests.