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A chronic inhalation study of a test toner, TiO2, and crystalline silica was conducted by exposure of groups of Syrian golden hamsters (strain: Han:AURA) for 6 h/day, 5 days/wk for 18 mo. Subsequently, the animals inhaled clean air only for an additional period of 5 mo. The target test aerosol exposure concentrations were 1.5, 6, and 24 mg/m3 for the test toner, 40 mg/m3 for TiO2, and 3 mg/m3 for SiO2. The latter two materials were used as negative and positive controls for fibrogenicity. The aerosol concentrations were charged to 4, 16, and 64 mg/m3 for toner (referred to as toner low, toner medium, and toner high) and 30 mg/m3 for TiO2 after 5 mo, in order to achieve the disired lung burdens. Inhalation of the test toner or the control materials showed no signs of overt toxicity.

Male and female Syrian golden hamsters were exposed 6h/day, 5 days/wk for up to 18 month to a special test toner, TiO2, and crystalline silica. The mass median aerodynamic diameters (MMAD) were about 4.0 mikro m for toner, 1.1 mikro m for TiO2, and 1.4 mikro m for silica. The target test aerosol exposure concentrations during the first 5 mo were 1.5, 6, and 24 mg/m3 (called toner low, toner medium, and toner high) for the test toner, 40 mg/m3 for TiO2, and 3 mg for SiO2. They were changed to 4, 16 and 64 mg/m3 for toner and 30 mg/m3 for TiO2 after 5 mo in order to achieve the desired lung burdens.

It is generally agreed that the biodurability of man-made vitreous fibers is a major factor for the characterization of potential health effects. As there is currently no standardization of experimental protocols to determine biodurability, the results of the clearance assays have not been used up to now for regulatory purposes. Methods used to analyze biodurability in animal models are short-term inhalational exposure and intratracheal instillation of rat respirable fibers. Both test methods have strengths and limitations for regulatory purposes. We outline recommended procedures for standardized biodurability assays that can be used to compare different fiber types. In animal experiments, biodurability is difficult to seperate from biopersistence, as mucociliary and macrophage-mediated clearance occur simultaneously with dissolution and disintegration. (Abstract truncated)

In an integrated project three different administration modes were compared in the rat: inhalation, intratracheal instillation and intraperitoneal injection. Further variables are the fibre type, the exposure time and the exposure dose. The final goal is to establish a standardized method to test fibrous particulates in animal experiments. Only the inhalation study is reported in this paper. Biopersistence of fibres is dependent on three main items: dissolution, mechanical disintegration and dislocation of fibres. Contribution of these processes for removal of fibres out of rat lungs was analysed by determination of the number of retained fibres and their length and diameter. Additionally, the macrophage-mediated clearance capacity was measured using tracer particles (46Sc2O3). the inflammatory potency of fibres was characterised by analysis of the bronchoalveolar lavage (BAL). Parts of the study are not totally completed. For fibre counts intermediate results are given.

Croups of 100 SPF Fischer-344 rats were exposed 6 h a day, 5d a week for 24 months to crystalline silica (1 mg . m-3, DQ 12 quartz) or titanium dioxide (5 mg . m-3) or air only. The animals were kept without further exposure for an additional 1.5 months. In the group exposed to crystalline silica a significantly increased incidence of 20 primary lung tumors was observed among 19 animals. The distribution of tumor types consisted of 3 adenomas, 11 adenocarcinomas, 4 benign cystic keratinizing squamous-cell tumors, 1 adenosquamous carcinoma, and 1 squamous-cell carcinoma. There were also 13 nodular hyperplasia lesions, which were interpreted to be borderline cases of adenomas. Approximately half of the adenoid tumors and all of the modular hyperplasia lesions were characterized by moderate central fibrosis (abstract truncated)

In a biopersistance study, Wistar rats inhaled three types of mineral fibres, i.e. glass fibres B-01/0.9; stone wool MMVF 21 (...); and ceramic fibres RCF 1 (...). Glass speres (...) were used as a negative control. After exposure, the animals were sacrificed at various dates and the lungs were analysed for fibre retention, deep lung clearance and lung histological alterations. In addition to these parameters, bronchoalveolar lavage was used as a suitable tool to estimate the biological effects of the various test substances on lungs. Lactic dehydrogenase, total protein, gamma-glutamyl transferase and glutathione titres were analysed in the lavage fluid on days 3, 17 and 31, repectively, post-exposure. The cellular response was evaluated by differential cell counting. (Abstract truncated)

From the present knowledge the biopersistence of fibres is a critical factor for the possible cancerogenic potency of these materials. To test the relationship between chemical composition, biopersistence and cancerogenicity, in the present study fibre materials were used most of which were tested already for carcinogenic potency in an intraperitoneal test or an inhalation study. These types of fibres were tested: glass microfibres M-475, M-753, E-Glas; glass wools MMVF11, TL, X607; M-Stone wool, M-Slag wool, ceramic fibre RCF1, glass fibre B-01 and polypropylene fibres. Respirable fractions of these materials were used. For the mineral wools special sizing techniques have been used to obtain these respirable fractions. The bivariate size distribution of fibres was analysed by scanning electron microscopy. (abstract truncated)

Methods for the determination of biodurability of man-made vitreous fibres are reviewed. For mineral wools the first step was the preparation of respirable fibre fractions. Fibres were administered to rats by inhalation or by intratracheal instillation. After serial sacrifice their lungs were digested by low-temperature ashing or by hypochlorite. The total number of fibres per lung and the distributions of length and diameter were analysed by electron microscopy. This resulted in a bivariate distribution of fibres at the various sacrifice dates. If the logarithm of the number of fibres decreased approximately linearly with time after exposure then the elimination kinetics of fibres can be characterized by a half-time. The half-times were compared between various experiments with rats exposed to mineral wool samples. In summary good agreement was found for the elimination of fibres after long-term inhalation and intratracheal instillation whereas shorter half-times were found after short-term inhalation.

Wollastonite is a naturally occuring calcium silicate which can break down into fibrous particles by the mechanical action of grinding. Since about 1950 wollastonite has been used extensively in the ceramics and plastics industries, and in some applications as a substitute for asbestos. Commercial samples of wollastonite have been used to prepare two fractions by aerosol separation techniques which according to the American Conference of Governmental Industrial Hygienists (ACGIH) can be deposited either throughout the human lungs or mainly in the alveolar area. In order to examine their bio-durability, these fractions were introduced intratracheally into rats. The distribution of the fibres in the lung was checked using a scanning electron microscope (SEM) 2 days after injection after sacrifice of animals. A relatively even distribution of fibres both in the bronchi as well as in the bronchioli and the alveoli was observed.

Hamsters (SG) were exposed 6 hours/day, 5 days/week for up to 18 months, to a special test toner at 0,4,16 or 64 mg/m³, TiO2 at 30 mg/m³ or SiO2 at 3 mg/m³ by the inhalation route, followed by a 5 months observation. The mean retained mass of toner, TiO2 and SiO2 at the termination of exposure were 0, 0.15, 0.87, 9.32 and 19.6 and 1.66 mg/ lung respectively. Mortality was lower than published values and causes of death were independent of treatment. There were no primary tumors of the usual epithelial types found in the lungs, nasal cavities and laryngo-pharynx of the control and toner exposed groups. Neuroendocrine cell hyperplasia and tumors were observed in the larynx and trachea which were independent of exposure. Interstitial fibrosis of a slight-very slight degree was observed in 49 per cent of toner medium, 83 per cent of toner high, 82 per cent of TiO2 and 91 per cent of SiO2 exposed groups. These responses, accompanied by the previously reported lung changes are ascribed to LU NG OVERLOAD. An increased frequ ency of squamous cell proliferative lesions of the forestomach was detected in all particulate exposed groups. Since all treatment groups were affected, and there was no dose response relationship among of the toner groups, the effect is non-specific and is of no predictive value for assessing human carcinogenicity.

The objective of this study was to investigate whether the effects if lung overloading are reversible upon cessation of a subchronic exposure to test toner. Female SPF F-344 rats were exposed 6hrs/day 5 days/week for 3 months to test toner at 0,10 and 40 mg/m3. Alveolar clearance of an 85 Sr-polystyrene tracer aerosol, and retention of the toner in lungs and lymph nodes were evaluated at the end of exposure and subsequently up to 15 months later. The retained quantity of test toner in the lungs at the end of exposure was 0.4 and 3 mg for the low and high exposure groups, respectively. 15 months later the corresponding values were 0.12 and 2.65 mg in the lungs. The alveolar clearance of the tracer aerosol was slightly retarded at the low and substantially impaired at the high exposure level. At the low exposure level, there was some recovery in the slowed clearance behaviour sixmonths post exposure. In contrast, at the high exposure level, there was no indication of a reversal of the im paired clearance. A kinetic model was developed to describe retention of test toner and of labelled particles in the lungs and in the lymph nodes. The assumptions are the following: The lung is divided into two compartments, which contain mobile and immobile macrophages, respectively. Macrophages with a particle burden above a critical volume are immobilized. By chemotaxis the nearest macrophages can migrate into the compartment of immobile macrophages. With this model all experimental data can be fitted well by only 5 parameters.