Search

The deposition characteristics in lungs following inhalation, the potential toxic effects induced and the toxicokinetic fate including a possible translocation to other sites of the body are predominantly determined by the agglomeration status of nanoscaled primary particles. Systemic particle effects, i.e. effects on remote organs besides the respiratory tract are considered to be of relevant impact only for de-agglomerated particles with a nanoscaled aspect. Rats were exposed to various types of nanoscaled particles, i.e. titanium dioxide, carbon black and constantan. These were dispersed in physiologically compatible media, e. g. phosphate buffer, sometimes including auxiliaries. Rats were treated with aqueous nanoparticle dispersions by intratracheal instillation or were exposed to well-characterized nanoparticle aerosols. Subsequently, alterations in the particle size distribution were studied using transmission electron microscopy (TEM) as well as the bronchoalveolar lavage (BAL) technique. Based on the results in various approaches, a tendency of nanoscaled particles to form larger size agglomerates following deposition and interaction with cells or the respiratory tract is predominant. The contrary trend, i.e. the increase of particle number due to a disintegration of agglomerates seems not to be of high relevance.

Mouse models for cystic fibrosis (CF) mimic intestinal manifestations of the human disease, but the lung disease phenotypes are lacking in most strains. In this work, the issue was addressed whether aging of the respiratory tract leads to lung pathophysiology in the exon 10 insertional mutant cftr(tm1Hgu) mouse. Weight gain, body weight and life-span of cftr(tm1Hgu) mice were significantly reduced compared with control mice. cftr(tm1Hgu) mice expressed 20, 21 or 37% (median) of wild-type cystic fibrosis conductance transmembrane regulator (cftr) mRNA transcript in lungs, intestine and kidney. Wild-type cftr mRNA in renal and respiratory epithelia varied with age from levels similar to Ztm:MF1 controls at the age of 2 and 4 months to levels seen in patients with CFTR splice mutations beyond the age of 6 months. The morphology of the bronchi and more distal airways was apparently normal in cftr(tm1Hgu) mice during their first year of life. The alveolar surfactant phospholipid pool was increased in cftr(tm1Hgu) mice by 1.5- to 2-fold compared with Ztm:MF1 controls. Alveolar clearance of gamma-labelled scandium oxide - the first report of lung clearance measurement in living mice - was reduced in cftr(tm1Hgu) mice compared with littermate controls. Although no progressive lung pathology was seen in the cftr expression of cftr(tm1Hgu) mice, surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were abnormal. Therefore, the described model is useful for studying the initial CF lung pathophysiology.

After subchronic exposure of rats to different fibre types [calcium magnesium silicate fibre, calcium magnesium zirconia silicate fibre, refractory ceramic fibre (RCF), non-fibrous material of that RCF and long amosite] lung fibre burden accumulation was proportional to biopersistence. The lung burden of non-fibrous particulate was so pronounced (>2µl/lung) that macrophage clearance collapsed and considerable inflammation occured. The effects of the three vitreous fibres also correlated with effects on clearance. A fibre (RCF) with the same composition as the particles accumulated to a similar mass/volume level but had less effect. Amosite fibres accumulated more than the other test materials investigated, mostly in the interstitial tissue, but produced only a small effect on clearance of labelled particles, however, amosite had the highest effect on cell proliferation. The toxicity results of this study are presented in an accompanying paper.

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.

Female Wistar rats were exposed in 6 m³ id groups and in increase in maternal lung weight in the high dose group. Consequently, a "no embryotoxic effect level" of 3 mg/m³ was determined. MDI metabolites occured in decreasing concentrations in the placenta, the fetus and the amniotic fluid. Further investigations are necessary to clarify the mechanism of the MDI-dependent tumor induction in the respiratory tract of the rat.

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.

At the same time that carcinogenicity of very thin glass fibers after interpleural and intraperitoneal (ip) administration was demonstrated (1,2) researchers found that gypsum fibers and HCI-leached chrysotile fibers were easily soluble in the peritoneal cavity. This led to the conclusion that the chemical composition of fibers was not responsible for the carcinogenesis but that the degree of carcinogenic potency of a fiber depended on the extent to which it retained its fibrous structure. A thin glass fiber with a low biodurability did not induce tumors after ip injection of a high dose, although the ip test had been criticized for being "overly sensitive". The ip model has been the most successful for determining carcinogenicity of inorganic fibers and establishing dose-response relationships; but to determine the possibilities and limitations of this test model, very high doses of nonfibrous silicon carbide and of a slightly durable glass fiber type were injected ip in Wistar rats.

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.