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In order to elucidate the pathology and mechanism of lung toxicity induced by chronic hair spray inhalation, male Wister rats 9 wk of age were exposed to a uniform concentration of hair spray for up to 12 wk using a jet nebulizer. The aerosol concentration to which the rats were exposed was about 7 g/m(3). Differential cell counts in bronchoalveolar lavage fluid (BALF), the expression of several cytokines from alveolar macrophage using the reverse-transcription polymerase chain reaction (RT-PCR) method, and histopathologic evaluation using a computer-aided graphic analyzer (IBAS) were conducted 1, 4, 8, and 12 wk after exposure. Over the passage of time, neutrophils and macrophages increased in BALF, and neutrophils infiltrated in the lung interstitium from the peribronchial interstitium to the alveolar septum. Alveolar macrophages showed increased expression of both the mRNA of tumor necrosis factor (TNF)-alpha and the mRNA of the chemokines macrophage inflammatory protein 2 (MIP2) and cytokine-induced neutrophil attractant (CINC). From these findings, chronic inhalation of hair spray is considered to induce at first intra-alveolar accumulation and activation of alveolar macrophages, followed by recruitment of neutrophils in the lung through the expression of proinflammatory cytokine, CINC, and MIP2, which cause predominantly neutrophilic inflammation in the lung.

Rats were exposed to 290 or 495 ppm methyl bromide gas for 6 h/day, 3 times/wk for 4 to 8 wk. Creatine kinase (CK), aspartate aminotransferase (ASAT), and lactate dehydrogenase (LDH) activities and bromide ion concentrations were measured in eight regions of the brain. Methyl bromide gas inhibited CK activities in all regions of the brain, though the inhibition tended to be smallest in the cerebellum (hemisphere and vermis) and largest in the brainstem (hypothalamus, midbrain, and medulla oblongata). The dose of methyl bromide to inhibit CK activities was lower than that to damage the central nervous system histologically. No inhibition of ASAT or LDH activities was seen except for a slight inhibition of these in striatum. Inhibition of CK activities did not increase clearly on increasing dose (290 to 495 ppm) or on prolonging exposure period (4 to 8 wk). Although 50% recovery of CK activities and the half-life of bromide ion agreed well in the medulla oblongata, changes in CK activities and bromide ion concentrations did not correlate otherwise. Thus, inhibition of CK activities in brain appears to be a sensitive indicator of methyl bromide intoxication, and may be related to genesis of its neurotoxicity. The inhibition seems to be caused by methyl bromide itself rather than by bromide ion. When effects on enzyme activities in brain homogenate were examined in vitro by bubbling with methyl bromide gas, CK inhibition was seen within 15 s of exposure. Dithiothreitol suppressed the CK inhibition, whereas N-acetylcysteine did not. These observations suggest that methyl bromide may attack sites in the CK molecule different from those attacked by ethylene oxide or acrylamide.

To investigate whether the results of intratracheal instillation studies on mineral fibers reflect the findings obtained by long-term inhalation data on mineral fibers, we have examined gene expression of cytokines and pathological features in lungs induced by intratracheal instillation and inhalation of mineral fibers. Male Wistar rats were given a single intratracheal instillation of 2 mg alumina silicate refractory fiber (RF1) or potassium octatitanate whisker (PT1), and were sacrificed 4 wk after the fiber instillation. Long-term inhalation studies were also performed. In these, animals were exposed to fiber aerosol of RF1 or PT1 for 5 days/wk for 1 yr, and sacrificed after 1 yr of inhalation. Expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and transforming growth factor-beta1 (TGF-beta1) from lungs was observed by reverse-transcription polymerase chain reaction (RT-PCR). The expression of TNF-alpha, IL-6, and TGF-beta1 mRNA in PT1-exposed lung was significantly higher than for those exposed to RF1 in both intratracheal instillation and inhalation studies. Pathological findings revealed that mild pulmonary fibrosis was seen in the lungs after intratracheal instillation and inhalation of PT1 but not RF1. Similarities were observed not only in gene expression of cytokines but in pathological features between both studies. These data suggested that the results of intratracheal instillation reflect the findings obtained from long-term inhalation data.

Effects on rats of a chronic inhalation exposure to glass fibers were examined histopatho-logically with special reference to pulmonary fibrosis and tumor genesis. Twenty-seven male Wistar rats of 6 wk of age were exposed to glass fibers, the exposure concentration was 2.2 ± 0.6 mg/m3, and the mass median aerodynamic diameter 2.6 mm (the geometric standard deviation 1.9), for I yr. Among them 6 and 9 rats were sacrificed just after the 1-yr exposure period and after a further l-yr clearance period, respectively. Among 25 control rats who did not undergo the exposure, 5 and 15 rats were sacrificed at the same time as each exposure group. Twelve exposure and five control rats died during the exposure and clearance period, respectively. No tumors were found in both the exposure and control rats immediately after the inhalations. There were no pneumoconiotic nodules or interstitial fibrosis in any of the rats, though a somewhat shorter survival was observed in the exposure group than in the control gr...

Carbon graphite whisker (CGW) was used in a 1-year inhalation study in male Wistar rats and its biological effect was observed until the 1-year clearance period. The inhalation study was conducted at 2.6 +/- 0.5 mg/m(3) (equivalent to 44.5 +/- 15.0 fibers/mL) for 6 hours a day, 5 days a week for 1 year. There were no differences in survival rate between the exposure and control groups during this examination; however, the body weights were significantly different at the end of the 1-year clearance. The lung weight at 3 days and 1 year after the end of exposure was not significantly different in both groups. The deposited amount of CGW was 6.83 +/- 0.75 mg at 3 days post-exposure; the deposition rate was 17.6%. Only around 30% of the total deposited CGW was cleared during the 1-year clearance period. The geometric means of CGW in the lung, i.e. CMD (count median diameter) and CML (count median length), hardly changed, and the clearance was delayed. In the histopathological examination, there was mild fibrosis in all exposed rats irrespective of the clearance period. One adenoma was observed in a single animal at 3 days post-exposure, while no adenomas were observed in the exposure group after the 1-year clearance. Epithelial hyperplasia was found in some animals.

Rats were exposed to a new graphite whisker for 4 wk by inhalation. Mass and fiber concentrations were 8.3 +/- 2.2 mg/m3 and 151.7 +/- 78.8 fibers (F)/ml, respectively, and mass median aerodynamic diameter was 3.0 micro m. Geometric mean sizes of the original whiskers were 0.86 micro m diameter and 6.8 micro m length. Size distributions, numbers, and mass of deposited whiskers in rat lungs were measured at 4 days, 7 mo, and 12 mo after the end of the exposure. Lungs including the whiskers were digested with acids by microwaves, then filtered onto polycarbonate filters. The number of whiskers on the filters was counted and sizes were measured based on scanning electron microphotos, and the mass was analyzed by an x-ray diffractometer. Change in the number of whiskers in the lung was expressed as an exponential decay with time, and the longer whiskers (20 micro m) tended to remain selectively in the lung after the 12-mo clearance. Mass of graphite whisker also decreased exponentially. Count median diameters and lengths (CMDs and CMLs) decreased gradually during clearance time, although CMDs did not decrease linearly. Morphological change of this whisker was very unique and characteristic; that is, the surface of the whiskers peeled away in the lung as a result of their stratified crystalline structure.