Ubiquitous fiber exposure in selected sampling sites in Europe.

OBJECTIVES: This study evaluates personal exposure to respirable inorganic and organic fibers during normal human lifetimes and assesses the order of magnitude of the contribution of inorganic fibers other than asbestos to total fiber exposure from man-made and natural sources. METHODS: Four groups (suburban schoolchildren, rural retired persons, office workers, and taxi drivers), with five persons per group, were monitored for 24 h four times during one year. Personal sampling pumps collected airborne dust on gold-precoated Nuclepore filters. The fibers were analyzed for fiber sizes specified by the World Health Organization. RESULTS: The geometric mean concentrations ranged from 9000 fibers.m-3 (office workers) to 20000 fibers.m-3 (schoolchildren) for organic fibers, and from 600 fibers.m-3 (taxi drivers) to 4000 fibers.m-3 (schoolchildren) for gypsum fibers. For other inorganic fibers the concentrations were around 5000 fibers.m-3. The contribution of fibers with an elemental composition similar to that of man-made vitreous fibers (MMVF) was less than about one-quarter of the content of other inorganic fibers. The fiber size distributions were uniform across the groups, and the organic fibers were the longest and thinnest nonasbestos fibers. CONCLUSIONS: Lifetime exposure to fibers can be ranked as organic fibers > other inorganic fibers > fibers with an elemental composition similar to MMVF > MMVF. Information on the biological effects of fibers is difficult to interpret for use in assessing the health risk from exposure to low levels of ubiquitous fibers, and there is a lack of knowledge on the effects of organic fibers.

Investigation on the biodurability of chemically different stone wool fibres.

The biodurability is one of the essential factors for a carcinogenic potential of mineral fibres. The in vivo solubility of commercial fibre products can be influenced by modifications of the chemical composition. Two types of experimental stone wool samples with new chemical composition were compared to a commercial stone wool sample. Sized fractions of these samples with median lengths of 7.1, 9.3 and 6.7 microns, respectively, and median diameters of 0.76, 1.02 and 0.63 microns, respectively, were intratracheally instilled into female Wistar rats with a single dose of 2 mg in 0.3 ml. 5 animals per group were sacrificed after 2 days, 1, 3, 6, 12 and 18 months. After low-temperature ashing of the lungs about 1,000 fibres per group and sacrifice date were analysed in SEM for length and diameter. The number of fibres in the total lung was calculated. An analysis of fibre number of different length and diameter fractions was used to estimate whether dissolution, breakage or mechanical clearance is responsible for the elimination of fibres from the lung. Results indicate that the breakage of fibres with length above 20 microns and the dissolution of fibres was faster in the experimental stone wool samples compared to the commercial sample.

Investigation on the durability of man-made vitreous fibers in rat lungs.

Two types of sized stonewool with median lengths of 6.7 and 10.1 microns and median diameters of 0.63 and 0.85 microns, and crocidolite with fibers of median length of 4.8 microns and median diameter of 0.18 microns were instilled intratracheally into female Wistar rats. A single dose of 2 mg in 0.3 ml saline was used for the stonewool samples and 0.1 mg in 0.3 ml saline for crocidolite. The evenness of distribution of fibers in the lung was checked by scanning electron microscopy (SEM). Five animals per group were sacrificed after 2 days, 1, 3, 6, and 12 months. After low-temperature ashing of the lungs about 200 fibers per animal were analyzed by SEM for length and diameter. The number and mass of fibers in the total lung were calculated. For the stonewool samples the decrease in the number of fibers in the lung ash followed approximately first order kinetics resulting in half-times of 90 and 120 days. The analysis of fiber number and diameter of different length fractions was used to estimate the contribution of three processes of fiber elimination: transport by macrophages for short fibers, breakage of fibers, and dissolution of fibers. (The process of transport by macrophages was found fastest for fibers with length < 2.5 microns). For the elimination of critical fibers with length > 5 microns, the breakage and dissolution were the most important processes. The breakage of fibers was predominant for one of the stonewool samples. The preferential type of the mechanism of fiber elimination is dependent on chemical composition and size distribution.

The problem of oncostatic specificity of cyclophosphamide (NSC-26271): Studies on reactions that control the alkylating and cytotoxic activity.

The relatively high oncostatic specificity of cyclophosphamide (CP) in vivo is shown to be due to the cytotoxic specificity of 4-hydroxycyclophosphamide (4-hydroxy-CP), the first product of metabolic activation of CP in the liver. This specificity can be evaluated not only in vivo by measuring the therapeutic index, but also in vitro by determining its cytotoxicity against Yoshida ascites tumor cells. Evidence is given that 4-hydroxy-CP is not an alkylating agent itself, but attains this property only by release of an alkylating N,N-(2-chloroethyl)phosphorodiamic acid moiety and acrolein. The energetic source for this rate-limiting toxication results from the resonance stabilization of the released acrolein. Reactions at the cryptoaldehyde group of 4-hydroxy-CP, which reduce or prevent the resonance stabilization of the 3-carbon unit to be released, lead to a deactivation of the primary metabolite of CP thus reducing or even preventing toxication, and hence influencing both the alkylating and cytotoxic activities of the molecule. Accordingly, it could be demonstrated by the reaction of 4-hydroxy-CP with thiols yielding 4-(S-R)-mercapto CP derivatives that the toxication of 4-hydroxy-CP can be controlled under physiologic conditions of pH and temperature. In the case of free protein sulfhydryl groups, this reaction also leads to fixation onto a macromolecule of the CP metabolite. On the basis of these peculiar reactivities of the oxazaphosphorine ring of 4-hydroxy-CP and of the partial reaction kinetics involved during toxication or deactivation, the significance of these findings to the problem of CP specificity is discussed.

Permeation of cyclophosphamide (NSC-26271) metabolites into tumor cells.

The permeation kinetics of cyclophosphamide and its metabolites were studied with Ehrlich ascites tumor cells, murine L1210 leukemia cells, and mouse L929 fibroblasts at 1 degrees C. In contrast to carboxyphosphamide and nor-nitrogen mustard, an equipartition of cyclophosphamide and 4-hydroperoxycyclophosphamide was observed in these cells. First experiments have been done to study the efflux of cyclophosphamide and 4-hydroperoxycyclophosphamide after incubation until saturation with Ehrlich ascites tumor cells. Cyclophosphamide could be washed out completely, whereas, 4-hydroperoxyclophosphamide shows an apparent retention in the cell at 37 degrees C.

Characterization of cyclophosphamide (NSC-26271) metabolites and related derivatives by field-desorption and electron-impact mass spectrometry.

Several important metabolites of cyclophosphamide (CP), such as 4-hydroxycyclophosphamide and phosphoramide mustard, some 4-alkyl(aryl)thio derivatives have been investigated by field-desorption and electron-impact mass spectrometry. The structural identification of synthetic compounds and of derivatives, isolated by thin-layer chromatography in vitro, was possible since complementary information can be obtained using the two ionization techniques. Whereas only the field-desorption mass spectra showed more abundant molecular ions, the electron-impact technique revealed a characteristic fragmentation pattern for most of the compounds studied. Examples are given which demonstrate the existence of stereoisomers of CP derivatives using thin-layer chromatography and field-desorption mass spectrometry. The results indicate that field-desorption mass spectrometry is also a particularly appropriate method for the characterization of unstable CP metabolites in vivo.