Estimation of Dissolution Rate From In Vivo Studies of Synthetic Vitreous Fibers

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.     

Response to Dr. Morfeld's Letter

Abstract

The biopersistence of airborne fibers is felt to play an important role in their potential toxicity. Since the dissolution rate of fibers can be measured in cell-free systems, the current study was undertaken to determine if the dissolution rate of fibers in the lung was related to the dissolution rate of fibers in vitro, and whether dissolution serves to remove fibers from the lung. To determine dissolution rates in vivo, suspensions of fibers were administered to rats by intratracheal instillation, and the numbers, lengths, and diameters of fibers recovered from the lungs at intervals up to 1 yr after administration were measured by phase-contrast optical microscopy. Five different glass fibers were used that had dissolution rates ranging from 2 to 600 ng/cm²/h measured in vitro in simulated lung fluid at pH 7.4. Examination of the diameter distributions of fibers longer than 20 μm showed that the peak diameter decreased steadily with time after instillation, at the same rate measured for each fiber in vitro, until it approached zero. Measurements of the total number of fibers remaining in the rats' lungs at times up to 1 yr after instillation suggest that not many of the administered fibers were being cleared by macrophage-mediated transport via the conducting airways. A computer simulation of the fibers in the lungs was performed in which each of the administered long fibers (20 μm or longer) was decreased in diameter according to the rate measured in vitro, while the short fibers (less than 20 μm long) were unaffected. The ratio of long to short fibers predicted by this simulation agreed well with this quantity measured from the fibers recovered from the rats' lungs at each time interval after instillation. It was concluded that long glass fibers, at least those longer than 20 μm, are removed from the lung by dissolution at much the same rate measured in vitro.     

A Comparison of Mathematical Methods for the Determination of In Vitro Dissolution Constants for Glass Fibers

Biopersistence plays a significant role in determining the potential bioactivity of respirable fibers. In vivo biopersistence in the lung is frequently assessed by in vitro fiber dissolution studies using simulated biological solutions and flow-through techniques. The dissolution rate (k) of a fiber is typically determined by elemental analysis of the flow-through solution to measure the mass of material leached from the fibers over a given time. Various methods may be used to estimate the value of k from these results. The present study compared the in vitro dissolution characteristics of seven experimental glass fiber compositions to those obtained for four recognized fiber compositions (MMVF 10-glass fiber; MMVF 11-glass fiber; MMVF 21-rockwool fiber; crocidolite fiber). Fiber dissolution was examined over a 17-wk period using a flow-through system designed to simulate the conditions encountered by fibers in the extracellular environment of the lung. Mass loss and changes in fiber diameter were determined over time and were then used to calculate k using five different methods. Although the selected methodologies did not produce identical estimations of k for each fiber, the resulting ranking of fiber solubility for each method was consistent. The seven experimental glass fibers were found to have k values intermediate between those of MMVF 11 and MMVF 21.     

A comparison of mathematical methods for the determination of in vitro dissolution constants for glass fibers

Biopersistence plays a significant role in determining the potential bioactivity of respirable fibers. In vivo biopersistence in the lung is frequently assessed by in vitro fiber dissolution studies using simulated biological solutions and flow-through techniques. The dissolution rate (k) of a fiber is typically determined by elemental analysis of the flow-through solution to measure the mass of material leached from the fibers over a given time. Various methods may be used to estimate the value of k from these results. The present study compared the in vitro dissolution characteristics of seven experimental glass fiber compositions to those obtained for four recognized fiber compositions (MMVF 10-glass fiber; MMVF 11-glass fiber; MMVF 21-rockwool fiber; crocidolite fiber). Fiber dissolution was examined over a 17-wk period using a flow-through system designed to simulate the conditions encountered by fibers in the extracellular environment of the lung. Mass loss and changes in fiber diameter were determined over time and were then used to calculate k using five different methods. Although the selected methodologies did not produce identical estimations of k for each fiber, the resulting ranking of fiber solubility for each method was consistent. The seven experimental glass fibers were found to have k values intermediate between those of MMVF 11 and MMVF 21.     

A CLEARANCE MODEL OF MAN-MAN VITREOUS FIBERS (MMVFs) IN THE RAT LUNG

Short-term inhalation experiments have been recently performed in rats to evaluate the biopersistence of man-made vitreous fibers (MMVFs). The number and size distribution of inhaled fibers in the rat lung were measured at different postexposure time points. These data were used for developing a mathematical model to describe the clearance kinetics of MMVFs in the rat lung. The model proposed a breakage scheme for long fibers during clearance. The breakage rates for different MMVFs were determined from the fiber size distribution data at different time points. The calculated breakage rate appears to be related to the in vitro dissolution rate; the more soluble a fiber, the faster the fiber breaks.     

ESTIMATING ROCK AND SLAG WOOL FIBER DISSOLUTION RATE FROM COMPOSITION

A method was tested for calculating the dissolution rate constant in the lung for a wide variety of synthetic vitreous silicate fibers from the oxide composition in weight percent. It is based upon expressing the logarithm of the dissolution rate as a linear function of the composition and using a different set of coefficients for different types of fibers. The method was applied to 29 fiber compositions including rock and slag fibers as well as refractory ceramic and special-purpose, thin E-glass fibers and borosilicate glass fibers for which in vivo measurements have been carried out. These fibers had dissolution rates that ranged over a factor of about 400, and the calculated dissolution rates agreed with the in vivo values typically within a factor of 4. The method presented here is similar to one developed previously for borosilicate glass fibers that was accurate to a factor of 1.25. The present coefficients work over a much broader range of composition than the borosilicate ones but with less accuracy. The dissolution rate constant of a fiber may be used to estimate whether disease would occur in animal inhalation or intraperitoneal injection studies of that fiber.     

Estimating rock and slag wool fiber dissolution rate from composition

A method was tested for calculating the dissolution rate constant in the lung for a wide variety of synthetic vitreous silicate fibers from the oxide composition in weight percent. It is based upon expressing the logarithm of the dissolution rate as a linear function of the composition and using a different set of coefficients for different types of fibers. The method was applied to 29 fiber compositions including rock and slag fibers as well as refractory ceramic and special-purpose, thin E-glass fibers and borosilicate glass fibers for which in vivo measurements have been carried out. These fibers had dissolution rates that ranged over a factor of about 400, and the calculated dissolution rates agreed with the in vivo values typically within a factor of 4. The method presented here is similar to one developed previously for borosilicate glass fibers that was accurate to a factor of 1.25. The present coefficients work over a much broader range of composition than the borosilicate ones but with less accuracy. The dissolution rate constant of a fiber may be used to estimate whether disease would occur in animal inhalation or intraperitoneal injection studies of that fiber.     

A new in vitro cellular system for the analysis of mineral fiber biopersistence

The toxicity of mineral fibers, whether they are natural or man made (MMMF), is usually evaluated in vivo using biopersistence tests in rodents. Development of an in vitro cellular model would be worthwhile in order to reduce, refine and finally replace animal models. For this purpose, we developed an in vitro assay using human monocytic cell line (U-937) to evaluate a new manufactured rock wool fiber (HDN) biodegradation. Experiments on earlier known mineral fibers asbestos (crocidolite) and glass wool fibers (CM44) were also performed. U-937 responded to HDN and CM44 only if they were activated. Among the different activators we used, Escherichia coli living cells as well as FS were the most efficient as evidenced by alterations of HDN and CM44 surface, detected by scanning electron microscopy, and by the measure of silicon released from the rock wool fibers. Asbestos fibers were not degraded when incubated in the presence of living bacteria. The MMMF modifications were function of the fiber composition, the time of exposure to activated cells and the concentration of activators. The pattern of MMMF degradation by our in vitro system was in accordance with those observed in an in vivo study, thus indicating that the fiber degradation by macrophage cells activated by E. coli living cells as well as FS is a valuable system to assess mineral fibers' biopersistence.     

Synthetic vitreous fibers: a review of toxicology research and its impact on hazard classification

Because the inhalation of asbestos, a naturally occurring, inorganic fibrous material, is associated with lung fibrosis and thoracic cancers, concerns have been raised about the possible health effects of synthetic vitreous fibers (SVFs). SVFs include a very broad variety of inorganic fibrous materials with an amorphous molecular structure. Traditionally, SVFs have been divided into three subcategories based on composition: fiberglass, mineral wool (rock, stone, and slag wools), and refractory ceramic fiber. For more than 50 years, the toxicologic potential of SVFs has been researched extensively using human epidemiology and a variety of laboratory studies. Here we review the research and its impact on hazard classification and regulation of SVFs. Large, ongoing epidemiology studies of SVF manufacturing workers have provided very little evidence of harmful effects in humans. Several decades of research using rodents exposed by inhalation have confirmed that SVF pulmonary effects are determined by the "Three D's", fiber dose (lung), dimension, and durability. Lung dose over time is determined by fiber deposition and biopersistence in the lung. Deposition is inversely related to fiber diameter. Biopersistence is directly related to fiber length and inversely related to fiber dissolution and fragmentation rates. Inhaled short fibers are cleared from the lung relatively quickly by mobile phagocytic cells, but long fibers persist until they dissolve or fragment. In contrast to asbestos, most of the SVFs tested in rodent inhalation studies cleared rapidly from the lung (were nonbiopersistent) and were innocuous. However, several relativley biopersistent SVFs induced chronic inflammation, lung scarring (fibrosis), and thoracic neoplasms. Thus, biopersistence of fibers is now generally recognized as a key determinant of the toxicologic potential of SVFs. In vitro dissolution of fibers in simulated extracellular fluid correlates fairly well with fiber biopersistence in the lung and pulmonary toxicity, but several exceptions suggest that biopersistence involves more than dissolution rate. Research demonstrating the relationship between biopersistence and SVF toxicity has provided a scientific basis for hazard classification and regulation of SVFs. For a nonhazardous classification, legislation recently passed by the European Union requires a respirable insulation wool to have a low lung-biopersistence or be noncarcinogenic in laboratory rats. U.S. fiberglass and mineral wool industries and the Occupational Health and Safety Administration (OSHA) have formed a voluntary Health and Safety Partnership Program (HSPP) that include: a voluntary permissible exposure level (PEL) in the workplace of 1 fiber/cc, a respiratory protection program for specified tasks, continued workplace air monitoring, and, where possible, the development of fiber formulations that do not persist in the lung. RCF manufacturers have implemented a Product Stewardship Program that includes: a recommended exposure guideline of 0.5 fibers/cc; a 5-year workplace air monitoring program; and research into the development of high-temperature-resistant, biosoluble fibers.     

BIOPERSISTENCE OF SYNTHETIC MINERAL FIBERS AS A PREDICTOR OF CHRONIC INTRAPERITONEAL INJECTION TUMOR RESPONSE IN RATS

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997), in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 µm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic intraperitoneal (ip) results is presented in detail. Analysis of the relationship of biopersistence clearance half-times to ip tumor response shows a statistically significant relationship of ip tumor response to not only the number of fibers injected, but also the median length of the fibers injected and their solubility (clearance half-time). The results show that the biopersistence half-times as determined by intratracheal instillation (T 1/2 of WHO fibers or weighted T 1/2 of fibers with L > 20 µm) and as determined by inhalation (weighted T 1/2 of fibers with L > 20 µm) are equivalent predictors of the ip results. From these ip studies, fibers that can be exonerated from classification as carcinogens in Europe have a relative tumorigenic potency in the ip cavity of between 66 and 2500 times less than fibers that have been shown to produce a significant increase in tumors following chronic inhalation exposure. In addition, based upon the ip results, there is no statistical difference between the EC and the other fiber exoneration criteria, such as the German Gefahrstoffverordnung of 1999.     

Estimating in vitro glass fiber dissolution rate from composition

A method is presented for calculating the dissolution rate constant of a borosilicate glass fiber in the lung, as measured in vitro, from the oxide composition in weight percent. It is based upon expressing the logarithm of the dissolution rate as a linear function of the composition. It was found that the calculated dissolution rate constant agreed with the measured value within the variation of the measured data in a set of compositions in which the dissolution rate constant ranged over a factor of 100. The method was shown to provide a reasonable estimate of dissolution over a considerably wider range of composition than what was used to determine the parameters, such as a set of data in which the dissolution rate constant varied over a factor of 100,000. The dissolution rate constant may be used to estimate whether disease would ensue following animal inhalation or intraperitoneal studies.     

ESTIMATING IN VITRO GLASS FIBER DISSOLUTION RATE FROM COMPOSITION

A method is presented for calculating the dissolution rate constant of a borosilicate glass fiber in the lung, as measured in vitro, from the oxide composition in weight percent. It is based upon expressing the logarithm of the dissolution rate as a linear function of the composition. It was found that the calculated dissolution rate constant agreed with the measured value within the variation of the measured data in a set of compositions in which the dissolution rate constant ranged over a factor of 100. The method was shown to provide a reasonable estimate of dissolution over a considerably wider range of composition than what was used to determine the parameters, such as a set of data in which the dissolution rate constant varied over a factor of 100,000. The dissolution rate constant may be used to estimate whether disease would ensue following animal inhalation or intraperitoneal studies.     

Toxicological and epidemiological studies on effects of airborne fibers: Coherence and public health implications

Airborne fibers, when sufficiently biopersistent, can cause chronic pleural diseases, as well as excess pulmonary fibrosis and lung cancers. Mesothelioma and pleural plaques are caused by biopersistent fibers thinner than ～0.1 μm and longer than ～5 μm. Excess lung cancer and pulmonary fibrosis are caused by biopersistent fibers that are longer than ～20 μm. While biopersistence varies with fiber type, all amphibole and erionite fibers are sufficiently biopersistent to cause pathogenic effects, while the greater in vivo solubility of chrysotile fibers makes them somewhat less causal for the lung diseases, and much less causal for the pleural diseases. Most synthetic vitreous fibers are more soluble in vivo than chrysotile, and pose little, if any, health pulmonary or pleural health risk, but some specialty SVFs were sufficiently biopersistent to cause pathogenic effects in animal studies. My conclusions are based on the following: 1) epidemiologic studies that specified the origin of the fibers by type, and especially those that identified their fiber length and diameter distributions; 2) laboratory-based toxicologic studies involving fiber size characterization and/or dissolution rates and long-term observation of biological responses; and 3) the largely coherent findings of the epidemiology and the toxicology. The strong dependence of effects on fiber diameter, length, and biopersistence makes reliable routine quantitative exposure and risk assessment impractical in some cases, since it would require transmission electronic microscopic examination, of representative membrane filter samples, for determining statistically sufficient numbers of fibers longer than 5 and 20 μm, and those thinner than 0.1 μm, based on the fiber types.     

Indices of fiber biopersistence and carcinogen classification for synthetic vitreous fibers (SVFs)

It is generally accepted that the biopersistence of a synthetic vitreous fiber (SVF) is an important determinant of its biological activity. Experimental protocols have been developed to measure the biopersistence of an SVF from short-term inhalation experiments with rats. Clearance kinetics of long (>20 microm) fibers (those believed to have greatest biological activity) have been approximated by one- or two-pool models. Several measures or indices of biopersistence have been proposed in the literature of which three, the weighted half-time (WT(1/2)), the time required to clear 90% of long fibers (T(0.9)), and the so-called slow-phase half-time (T(2)), have been investigated in some detail. This paper considers both one- and two-pool models for long fiber clearance, characterizes the properties of these candidate indices of fiber biopersistence, identifies measures with potentially superior statistical properties, suggests possible cutoff values based on the relation between biopersistence and the outcome of chronic bioassays, and offers comments on the selection of efficient experimental designs. This analysis concludes that WT(1/2) and T(0.9) are highly correlated, are efficient predictors of the outcome of chronic bioassays, and have reasonable statistical properties. T(2), although perhaps attractive in principle, suffers from some statistical shortcomings when estimated using present experimental protocols. The WT(1/2) is shown to be directly proportional to the cumulative exposure (fiber days) after the cessation of exposure and also the mean residence time of these fibers in the lung.     

The role of fiber durability/biopersistence of silica-based synthetic vitreous fibers and their influence on toxicology

This work summarizes what is known about the role of fiber durability/biopersistence of silica-based synthetic vitreous fibers (SVFs) and their influence on toxicology. The article describes the key processes leading from exposure to biological effect, including exposure, pulmonary deposition, clearance by various mechanisms, accumulation in the lung, and finally possible biological effects. The dose-dimension-durability paradigm is used to explain the key determinants of SVF toxicology. In particular, the key role played by the durability/biopersistence of long (>20microm) fibers is highlighted. Relevant literature on the prediction of in-vitro dissolution rates from chemical composition is summarized. Data from in-vitro and in-vivo durability/biopersistence tests show that these measures are highly correlated for long fibers. Both durability and biopersistence are correlated with the outcome of chronic inhalation bioassays. A schematic approach is presented for the design and testing of new SVFs with lower biopersistence.     

The biopersistence of brazilian chrysotile asbestos following inhalation

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.     

Toxicokinetics and effects of fibrous and nonfibrous particles

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.     

Synthetic vitreous fibers: a review toxicology, epidemiology and regulations

This review addresses the characteristics which differentiate synthetic vitreous fibers (SVFs, e.g., fiber glass, stonewool, slagwool, refractory ceramic fibers, etc.), how these influence the potential biopersistence and toxicity, the most recent epidemiological results and the integration of these findings into the health and safety regulations in Europe and the United States. Also presented is the historical basis for the European classification directive. The use and equivalence of the chronic inhalation toxicology and chronic intraperitoneal injection studies in laboratory rodents for evaluation of fiber toxicology is assessed as well as the impact of dose selection and design on the validity of the study. While synthetic vitreous fibers can span a wide range of chemistries, recognition and understanding of the importance of biopersistence (ability to persist in the lung) in fiber toxicity has led to the development of more and more biosoluble fibers (that break down rapidly in the lung). Still, the epidemiological data available which are largely based upon the use of fibers in past decades, indicate that the SVF do not present a human health risk at current exposure levels. The animal toxicology and biopersistence data provide a coherent basis for understanding and evaluating the parameters which affect SVF toxicity. The current regulations are based upon an extensive knowledge base of chronic studies in laboratory rodents which confirm the relationship between chronic adverse effects and the biopersistence of the longer fibers that can not be fully phagocytised and efficiently cleared from the lung. The amorphous structure of synthetic vitreous fibers facilitates designing fibers in use today with low biopersistence. Both the epidemiological data and the animal studies database provide strong assurance that there is little if any health risk associated with the use of SVFs of low biopersistence. IARC (2001) reclassified these fibers from Category 2b to Category 3 (with RCF and special purpose fibers remaining in 2b) an event which has not been common in the history of these monographs.     

Synthetic Vitreous Fibers: A Review Toxicology,Epidemiology and Regulations

This review addresses the characteristics which differentiate synthetic vitreous fibers (SVFs, e.g., fiber glass, stonewool, slagwool, refractory ceramic fibers, etc.), how these influence the potential biopersistence and toxicity, the most recent epidemiological results and the integration of these findings into the health and safety regulations in Europe and the United States. Also presented is the historical basis for the European classification directive. The use and equivalence of the chronic inhalation toxicology and chronic intraperitoneal injection studies in laboratory rodents for evaluation of fiber toxicology is assessed as well as the impact of dose selection and design on the validity of the study. While synthetic vitreous fibers can span a wide range of chemistries, recognition and understanding of the importance of biopersistence (ability to persist in the lung) in fiber toxicity has led to the development of more and more biosoluble fibers (that break down rapidly in the lung). Still, the epidemiological data available which are largely based upon the use of fibers in past decades, indicate that the SVF do not present a human health risk at current exposure levels. The animal toxicology and biopersistence data provide a coherent basis for understanding and evaluating the parameters which affect SVF toxicity. The current regulations are based upon an extensive knowledge base of chronic studies in laboratory rodents which confirm the relationship between chronic adverse effects and the biopersistence of the longer fibers that can not be fully phagocytised and efficiently cleared from the lung. The amorphous structure of synthetic vitreous fibers facilitates designing fibers in use today with low biopersistence. Both the epidemiological data and the animal studies database provide strong assurance that there is little if any health risk associated with the use of SVFs of low biopersistence. IARC (2001) reclassified these fibers from Category 2b to Category 3 (with RCF and special purpose fibers remaining in 2b) an event which has not been common in the history of these monographs.     

IN VITRO MEASUREMENT OF FIBER DISSOLUTION RATE RELEVANT TO BIOPERSISTENCE AT NEUTRAL pH: AN INTERLABORATORY ROUND ROBIN

Measurements are presented of the dissolution rates in neutral pH simulated lung (SLF) of several man-made vitreous fibers (MMVF) and crocidolite asbestos that were recently in chronic rodent inhalation studies. The measured dissolution rate depended strongly on the fiber composition. The MMVF tested dissolved from 30 times to nearly 1000 times faster than the crocidolite asbestos. Measurements were made in flow-through equipment in four different laboratories in North America and Europe. The standard deviations of the measured values for each fiber were typically between 30 and 50% of average value. It is believed that in order to be relevant to the dissolution of long fibers the extracellular fluid of the lung, the in vitro measurement must be performed at a rate high enough that corrosion products do not accumulate in sufficient concentration affect the dissolution rate.