Walter Eastes

A Mathematical Model of fiber Carcinogenicity and Fibrosis in Inhalation and Intraperitoneal Experiments in Rats

AbstractA hypothesis is presented that predicts the incidence of tumors and fibrosis in rats exposed to various types of rapidly dissolving fibers in an inhalation study or in an intraperitoneal (ip) injection experiment, for which the response to durable fibers has been determined. The model takes into account the fiber diameter and the dissolution rate of fibers longer than 20 μm in the lung, and it predicts the measured tumor and fibrosis incidence to within approximately the precision of the measurements. The basic concept of the model is that a rapidly dissolving long fiber has the same response in an animal bioassay as a much smaller dose of a durable fiber. Long, durable fibers are considered to have special significance since no effective mechanism is known by which these fibers may be removed. In particular, the hypothesis is that the effective dose of a dissolving long fiber scales as the residence time of that fiber in the extracellular fluid. For example, a certain dose of a fiber that dissolv...

Dissolution of Glass Fibers in the Rat Lung Following Intratracheal Instillation

AbstractThe 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 f...

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.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.

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.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.

FIBER DIAMETER DISTRIBUTIONS IN TYPICAL MMVF WOOL INSULATION PRODUCTS

In order to make available a consistent set of information about the fiber diameter distribution in man-made vitreous fiber (MMVF) products, we measured the length-weighted fiber diameter distribution in 22 samples of glass wool, rock and slag wool, refractory ceramic fiber, and special purpose fiber Insulation, from 11 different manufacturers. All of the samples were measured by the same procedures using light microscopy (LM), scanning electron microscopy (SEM), and gas adsorption (the BET method). We found that the length-weighted fiber diameters were neither approximately normally nor log normally distributed with arithmetic standard deviations typically 50–100% of the arithmetic mean. The geometric mean diameter was usually significantly smaller than the arithmetic mean diameter and the length-weighted median diameter lay between these two means. There was good agreement between the various means and standard deviations measured by LM and by SEM. In addition, the BET-measured fiber specific surface ar...

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 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.

The durability and distribution of glass fibres in the rat following intra-peritoneal injection

Intra-peritoneal (IP) injection is being recommended as a means of assessing potential carcinogenicity of MMF following inhalation. Little is known of the behaviour of fibres in the peritoneal cavity or its relevance to the lung. This study considered both the biopersistence and the distribution of dose following IP injection of fibres. Biopersistence of fibres in the peritoneal cavity has been compared with that observed previously in the lung. Marked differences were found, with long fibres (> 20 microns) being more durable in the peritoneal cavity than in the lung. Breakage could not account for this finding, whereas differences in dissolution could. The behaviour of fibres and powders and their distribution in the peritoneal cavity following injection of different masses is reported. Distribution of dose depended on injection mass, with masses of < 1.5 mg showing even uptake onto the surfaces of the peritoneal organs, and higher masses resulting in the development of nodules of injection material, free in the peritoneal cavity, or loosely bound to the peritoneum. With fine powder, some clearance was observed over the first 48 h after IP injection, but not with fibres. The findings on both durability and distribution of dose following IP injection have implications on the justification for the use of IP injections in assessment of potential carcinogenicity of fibres following inhalation.

AIRBORNE GLASS FIBER CONCENTRATIONS DURING INSTALLATION OF RESIDENTIAL INSULATION

In an effort to better characterize airborne fiber levels associated with the installation of residential insulation and to determine the proportion of airborne fibers that are glass fibers, airborne fiber concentrations were measured during the installation of several Owens-Corning Fiberglas insulation products. Sample collection and fiber counting procedures followed National Institute for Occupational Safety and Health Method 7400 with some modifications to allow identification of the fiber type. The arithmetic mean concentration of total airborne fibers during installation of batt-type insulation was 0.22 fibers per cubic centimeter (f/cc) (95% confidence limits of 0.18–0.27 f/cc). Significantly, approximately 60% of these total fibers were glass fibers and approximately 20% were respirable glass fibers. For applications of blowing wool, the total airborne fiber concentrations were higher, with means of 1.0 f/cc (0.9–1.1) or 2.1 f/cc (15–2.7), depending on the product type. Glass fibers were 0.7 f/cc ...

Do vitreous fibers break in the lung

In order to determine whether breakage of long vitreous fibers in the lung could be responsible for removing significant numbers of these fibers, an intratracheal instillation study was done with a preparation consisting of mostly long fibers of two different types. Following instillation of both fibers, laboratory rats were sacrificed at 6 times up to 14 days. The NK (conventional borosilicate glass) fiber preparation had about 20% short fibers (length ≤ 15 μm) initially, and fibers recovered from the lungs remained at that proportion for the entire 14 days. But the HT (a new rock or stone wool) fiber preparation, which had about 5% short fibers initially, jumped to about 50% short fibers at 2 days and remained at that proportion for the rest of the study. The appearance of many short HT fibers where there were few initially is conclusive evidence that these long fibers break, and it explains their rapid removal from the lung. Since the HT fibers dissolve rapidly at acid pH, but slowly at the near neutral pH of the extracellular lung fluid, it is likely that acid attack by phagocytic cells is causing the long fibers to dissolve and break. The long NK fibers dissolve rapidly at neutral pH but slowly at acid pH and thus appear to clear by more or less uniform dissolution without apparent breakage. The long fibers of these two kinds are removed rapidly at about the same rate, but by a different mechanism.

Fiber glass and rock/slag wool exposure of professional and do-it-yourself installers.

The fiber glass (FG) and rock/slag wool (RSW) manufacturers have developed a Health and Safety Partnership Program (HSPP) with the participation and oversight of the Occupational Safety and Health Administration (OSHA). Among its many provisions the HSPP includes the continuing study of FG and RSW workplace concentrations in manufacturing facilities operated by FG/RSW producers and among their customers and end users. This analysis estimates the probable cumulative lifetime exposure (fiber-months/cubic centimeter [f-months/cc]) to those who install FG and RSW insulation in residential, commercial, and industrial buildings in Canada and the United States. Both professional and do-it-yourself (DIY) cohorts are studied and the estimated working lifetime exposures are compared with benchmark values derived from an analysis of the epidemiological studies of FG and RSW manufacturing cohorts. The key finding of this analysis is that both of these end-user cohorts are likely to have substantially lower cumulative lifetime exposures than the manufacturing cohorts. As the most recent updates of the epidemiological studies concluded that there was no significant increase in respiratory system cancer among the manufacturing cohorts, there is likely to be even less risk for the installer cohorts. This analysis also underscores the wisdom of stewardship activities in the HSPP, particularly those directed at measuring and controlling exposure.