(2010) The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short-term inhalation exposure: interim results, Inhalation Toxicology, 22:11,
The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods.The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos.
To support clinical development of S-nitrosoglutathione (GSNO) as a therapeutic agent, 28-day toxicology studies in rats and dogs were conducted. Rats (21-25/sex) and dogs (3-5/sex) were exposed for 4 hours or 1 hour, respectively, to inhaled GSNO (0, 3, 9.3, 19, and 28 mg/kg per d in rats and 0, 4.6, 9.0, and 16.2 mg/kg per d in dogs) or vehicle daily via a nebulizer. Animals were monitored throughout the 28-day dosing period and during a postexposure recovery period. Complete necropsy and tissue examinations were performed. Experimental end points included clinical pathology, toxicokinetics, and immunotoxicology. No biologically significant adverse findings were noted in either species, and the no observed adverse effect levels (NOAELs) under these conditions were the highest achieved doses (28 and 16.2 mg/kg per d in rats and dogs, respectively). These data demonstrate that GSNO is well tolerated in rodents and dogs and predict a favorable toxicity profile in humans, thus supporting future clinical development of GSNO or closely related compounds.
Inhalation of vanadium pentoxide clearly increases the incidence of
alveolar/bronchiolar neoplasms in male and female B6C3F1 mice at all
concentrations tested (1, 2 or 4 mg/m3), whereas responses in F344/N
rats was, at most, ambiguous. While vanadium pentoxide is mutagenic in
vitro and possibly in vivo in mice, this does not
explain the species or site specificity of the neoplastic response. A nose-only
inhalation study was conducted in female B6C3F1 mice (0, 0.25, 1 and
4 mg/m3, 6 h/day for 16 days) to explore histopathological,
biochemical (α-tocopherol, glutathione and F2-isoprostane) and genetic (comet
assays and 9 specific DNA-oxo-adducts) changes in the lungs. No treatment
related histopathology was observed at 0.25 mg/m3. At 1 and
4 mg/m3, exposure-dependent increases were observed in lung
weight, alveolar histiocytosis, sub-acute alveolitis and/or granulocytic
infiltration and a generally time-dependent increased cell proliferation rate of
histiocytes. Glutathione was slightly increased, whereas there were no
consistent changes in α-tocopherol or 8-isoprostane F2α. There was no evidence
for DNA strand breakage in lung or BAL cells, but there was an increase in
8-oxodGuo DNA lesions that could have been due to vanadium pentoxide induction
of the lesions or inhibition of repair of spontaneous lesions. Thus, earlier
reports of histopathological changes in the lungs after inhalation of vanadium
pentoxide were confirmed, but no evidence has yet emerged for a genotoxic mode
of action. Evidence is weak for oxidative stress playing any role in lung
carcinogenesis at the lowest effective concentrations of vanadium pentoxide.
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