Metabolism and pulmonary toxicity of butylated hydroxytoluene (BHT).
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Animals↗
Biomedical subjects
H Witschi
Publications and source records attributed to H Witschi.
Effects of glycerol on lung and liver tumor development.
Mice of several strains (A/J, SWR, MaMyJ, BALB/cByJ, 129J, and C57BL/6J) were treated with the carcinogens 3-methylcholanthrene, urethane, and 4-nitroquinoline 1-oxide and then given 1 or 5% glycerol in the drinking water for up to 4 months. Effects of glycerol on lung tumor multiplicity and incidence were evaluated. The effects of glycerol were variable, and in the majority of experiments glycerol failed to enhance tumor development in mouse lung. Analysis of cell kinetics did not show a proliferative response of alveolar or bronchiolar cells to glycerol. In rats, glycerol did not enhance the appearance of putative preneoplastic liver foci, and in C3H mice it did not increase the incidence of spontaneously occurring liver tumors. It is concluded that glycerol does not increase number or incidence of lung tumors in the mouse strains used, whether the animals are pretreated with a carcinogen or not. Glycerol does not affect liver tumor development.
Animals↗
Modulation of lung tumor development in mice with the soybean-derived Bowman-Birk protease inhibitor.
Male strain A mice were treated with a single i.p. injection of 3-methylcholanthrene (MCA). Four months later, the number of lung tumors was counted. In mice treated three times a week, for 8 weeks, with crude soybean extract containing the Bowman-Birk protease inhibitor (BBI), the number of lung tumors was significantly lower than in control animals receiving carcinogen treatment only (40-70% of controls). On the other hand, treatment initiated 8 weeks after MCA only had no effect on tumor development. A reduction in the number of lung tumors was also found in animals treated i.p. or orally with purified BBI three times a week for 8 weeks following MCA administration. It is concluded that BBI is capable of partially blocking the development of lung tumors in mice.
Animals↗
Progressive lung injury over a one-year period after a single inhalation exposure to beryllium sulfate.
The chronic pulmonary toxicity of beryllium sulfate was examined in rats over a 1-yr period after a single, 1-h exposure. Male rats, exposed in a nose-only inhalation chamber to an aerosol of 4.05 micrograms Be/L, were evaluated for lung toxicity by the methods of bronchoalveolar lavage, lung cell kinetics, and histopathologic analysis. Bronchoalveolar lavage activities for alkaline phosphatase (Alk Pase) and acid phosphatase (Ac Pase) were elevated 3 wk after exposure; lactate dehydrogenase (LDH) and Alk Pase activities peaked 3 months after exposure. Histopathologic analysis revealed progressive focal interstitial pneumonitis with a prominent alveolar component of heteromorphic macrophages, neutrophils, and debris. No increase was noted in the overall labeling index in the alveolar cell population at any of the time points sampled. This study demonstrates the effectiveness of bronchoalveolar lavage fluid analysis in monitoring lung damage over a prolonged period and shows that the pulmonary toxicity of beryllium manifests itself as a progressive lesion from a single 1-h inhalation exposure to BeSO4.
Acid Phosphatase↗
Effects of hyperoxia on growth characteristics of metastatic murine tumors in the lung.
Suspensions of an oxygen-sensitive (MT-7) and of an oxygen-insensitive(M109) tumor cell line were injected i.v. into BALB/c mice. Exposure to 100% O2 after injection of the cells did not modify the initial arrest of either cell line in the lung. Exposure of animals given injections of MT-7 cells for 60 h to 100% oxygen decreased the number of lung colonies formed even when onset of oxygen exposure was delayed up to 10 days after injection of the cell suspension. Cell cycle time and growth fraction in lung colonies growing in vivo were estimated from an analysis of the percentage of mitoses labeled. In lung colonies formed by MT-7 cells, hyperoxia produced a mitotic delay and a 30 to 40% reduction in the growth fraction. In M109-derived colonies, oxygen did not change cell cycle times or reduce growth fraction. In earlier experiments done in vitro and reported by others it had been found that, in tumor cell lines other than the ones used in the present study, a prolongation of the early prophase was the most oxygen-sensitive event. The present data show that in vivo oxygen inhibits lung colony formation in MT-7 cells by a similar mechanism.
Animals↗
Oxygen tolerance in mice following exposure to butylated hydroxytoluene.
Adult BALB/c mice, which are sensitive to hyperoxia (LT50 = 4.5 days 100% O2), were made tolerant to 100% O2 after treatment with butylated hydroxytoluene (BHT). Following a single ip dose of 400 mg/kg, mice survived longer periods in O2 when exposed to O2 at 7, 14, and 21, but not 2 days, following BHT injection. The tolerance was most pronounced on Day 7 (LT50 = 9.6 days) and decreased with time (LT50 7.7 days on Day 14 and 7.3 days on Day 21). Glucose-6-phosphate dehydrogenase levels of whole lung homogenates following BHT exposure were elevated on Day 7 when expressed as per milligram of protein or DNA. Other antioxidant defenses were generally increased only when expressed on a per lung basis. Histopathology of lungs from BHT-treated mice revealed typical BHT-induced lung lesions. BHT treatment followed by long-term hyperoxic exposure produced additional damage to the lung manifested by the exudative phase of diffuse alveolar damage with 1 week of exposure. This was followed by the proliferative phase, then chronic interstitial pneumonitis and fibrosis with 2 and 6 weeks of exposure, respectively. Mice continued to survive in 100% O2 despite this damage. We conclude that pretreatment with BHT enhances O2 tolerance in mice, which may be mediated by induction of antioxidant defenses and also by cell renewal induced by BHT damage.
Animals↗
Ozone, nitrogen dioxide and lung cancer: a review of some recent issues and problems.
Lung cancer in man is a common disease. There is some recent concern that oxidant air pollutants might be a contributing risk factor. Experimental data show that ozone and NO2 increase incidence and multiplicity of lung tumors in strain A mice; however, the data are not always statistically significant. Also it depends on experimental design whether ozone enhances or inhibits the development of lung tumors in mice. Similarly, ozone and nitrogen dioxide enhance lung colonization by cancer cells injected intravenously following exposure to the air pollutants, whereas NO2 kills lung metastases if cells are injected prior to exposure. Both ozone and NO2 modulate the proliferation of pulmonary neuroendocrine cells, the precursor cells for small cell lung cancer. It is concluded that there is little evidence to implicate ozone or NO2 directly as pulmonary carcinogens, but that they might modify and influence the carcinogenic process in the lung.
Animals↗
Pulmonary toxicity of cytostatic drugs: cell kinetics.
Mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3H-labeled thymidine and autoradiography. In cyclophosphamide-treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2-3 weeks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature whereas in animals treated with oleic acid there was an initial burst of type II cell proliferation. It is concluded that the patterns of pulmonary repair vary between chemicals designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid.
Animals↗
Modification of gastrointestinal tumor development in rats by dietary butylated hydroxytoluene.
Male Fischer 344 rats were given two or four injections of 1,2-dimethylhydrazine (DMH), 40 mg/kg sc, and then fed a diet containing 0.5% butylated hydroxytoluene (BHT). Five months later, the animals treated with two doses of DMH had a significantly higher incidence of colon tumors than the animals fed a BHT-free control diet. In animals treated with four injections of DMH, the increase in colon tumor incidence was statistically not significant, but BHT appeared to produce a shift in tumor distribution. In a second experiment, Fischer 344 rats were treated with 2 X 40 mg/kg of DMH and fed a diet of 0.5 or 0.1% BHT for 6 months; these animals had a significantly increased incidence of small intestinal tumors (duodenum, jejunum, and ileum) compared with animals fed the control diet. In rats treated with DMH and given a diet of 0.5% butylated hydroxyanisole (BHA), overall incidence of gastrointestinal tract tumors was higher than in control animals, although the difference was statistically not significant. Administration of N-nitroso-N-methylurea (NMU; 90 mg/kg given orally) produced stomach and colon tumors; 0.5% BHT in the diet did not modulate tumor incidence. It is concluded that dietary BHT may enhance development of gastrointestinal tumors produced by DMH, but not by NMU, provided exposure to BHT occurs after exposure to the carcinogen.
Animals↗
Modification by ozone of lung tumor development in mice.
Mice, either strain A/J or Swiss Webster, were exposed for 18 weeks either to filtered air or to 0.4 or 0.8 ppm ozone for 8 hours daily. Subgroups in each test group received a single ip injection of 1,000 mg urethan/kg or 0.9% sodium chloride vehicle 1 day prior to initiation of the exposure regimen. Tumor incidence in Swiss Webster mice was 0-3% in groups not receiving urethan and was 61-74% in groups receiving urethan. In A/J mice, the corresponding values were 9-38% and 100%, respectively. Exposure to ozone caused a decrease in the number of tumors per lung in urethan-treated mice of both strains, in a dose-dependent manner. There seemed to be a specific decrease in tumors derived from alveolar type II cells in the A/J mice given urethan plus ozone. Most interesting, perhaps, was a significant increase in the number of tumors per lung in A/J mice exposed to 0.8 ppm ozone without urethan, confirming a previous report by others. The corresponding ozone effect on lung tumor development was not observed in Swiss Webster mice.
Air Pollution↗
Intratracheal versus intravenous administration of bleomycin in mice: acute effects.
We examined whether intratracheal instillation (IT) of bleomycin would produce similar or dissimilar lesions when compared to lung damage following intravenous (iv) injection of the drug. BALB/c mice were treated with either 4 U/kg IT or 100 U iv bleomycin and killed at intervals up to 21 days after treatment. Cell proliferation, histopathology, lung lavage, and hydroxyproline content were examined. There was a biphasic response in the cell proliferation in the IT-treated mice, while the iv-treated mice showed a single delayed peak in proliferation. The histopathologic features of interstitial pneumonitis, elevation of lung lavage enzyme activities, and lung hydroxyproline content were qualitatively similar between the two routes of administration, although the IT mice response was always greater in magnitude. Differences exist between the lung reaction to these two routes of administration, but these differences reflect nonspecific inflammatory response and magnitude of initial injury. We conclude that the response to bleomycin administered IT is basically similar to the changes produced by intravenous injection of the drug.
Animals↗
Patterns of cell proliferation during recovery from oxygen injury. Species differences.
Do rats, mice, hamsters, and marmosets respond differently to acute lung injury? Animals of each species were exposed to 100% oxygen for 48 h, then osmotic pumps, which released 3H-thymidine for a 1-wk period, were implanted. The labeling index (LI) (cells labeled/total cells counted) was increased in all 4 species. Repair in rats was manifested by a high LI, dominated by endothelial cell proliferation. Mice and hamsters had a lower LI, which was dominated by type II pneumocyte proliferation in mice, whereas in hamsters, macrophages and pneumocytes proliferated. The pattern of cell proliferation in marmosets most resembled that seen in mice.
Animals↗
Attenuation of pulmonary fibrosis in mice by aminophylline.
Cyclic nucleotides have been shown in vitro to regulate fibroblast proliferation and/or collagen production. We have reported previously that propranolol, which decreases the cAMP/cGMP ratio, potentiates the amount of fibrosis produced in a damaged lung. The purpose of this study was to determine if elevations in the cAMP/cGMP ratio may attenuate collagen production by fibroblasts following lung damage. Lung injury was induced in mice by either butylated hydroxytoluene (BHT) (350 or 400 mg/kg intraperitoneally) or bleomycin (4 units/kg intratracheally). The mice were treated with a phosphodiesterase inhibitor, aminophylline (20 mg/kg twice daily), prior to induction of lung injury and for the duration of the study. Cyclic nucleotide changes in the lung were also determined during lung injury, with and without aminophylline. The administration of aminophylline, which increased the cAMP/cGMP ratio, resulted in attenuation of the increase in total lung collagen normally seen after injury, while having no effect on collagen levels in the undamaged lung. The results are compatible with the hypothesis that elevation of whole lung cAMP/cGMP ratio early in the damage and repair process correlates with decreased hydroxyproline deposition.
Aminophylline↗
Mitochondrial injury of pulmonary alveolar epithelial cells in acute paraquat intoxication.
The primary ultrastructural changes in pulmonary alveolar epithelial cells are described in paraquat-injected rats. Within 6-12 hr a single intravenous injection of 40 mg/kg paraquat dichloride caused selective mitochondrial swelling and loss of intramitochondrial granules within 24 hr in alveolar Type II cells. As the mitochondrial injury advanced, microvilli disappeared from apical plasma membrane followed by a cell destruction and detachment from basement membrane. This was accompanied by secondary damage to Type II cells and interstitial cells. These results indicate that paraquat may affect primarily the Type II cells and the first lesion produced occurs in mitochondria.
Animals↗
Progressive pulmonary fibrosis in rats: a biochemical, cell kinetic, and morphologic analysis.
The concomitant treatment of rats with bleomycin and hyperoxia results in synergistic development of pulmonary injury. We exposed rats to 70% oxygen for 72 hr following an intratracheal instillation of bleomycin (0.2 U/kg body wt). Animals were killed 15, 30, 60 and 90 days after treatment for hydroxyproline, cell kinetics, and histopathologic analysis. A 16% increase in hydroxyproline over controls was seen 15 days after treatment which was manifested by the proliferation phase of diffuse alveolar damage and an increase in cell labeling by tritiated thymidine. Thirty days after treatment the hydroxyproline remained elevated while lung injury appeared to be healing with a residual focal interstitial pneumonitis and a drop in cell labeling. Between 60 and 90 days, there was an additional significant increase in hydroxyproline to 44% over controls. Diffuse interstitial pneumonitis with fibrosis was observed. Cell labeling remained constant between 60 and 90 days. We conclude that the treatment of rats with bleomycin and hyperoxia results in slowly progressive pulmonary fibrosis. The increase in hydroxyproline in the chronic phase was not accompanied by an increase in cell proliferation, and therefore may have resulted from an increase in cellular production of hydroxyproline rather than increased number of cells producing collagen.
Animals↗
The effect of 3-methylfuran inhalation exposure on the rat nasal cavity.
The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in female CD/CR rats. Animals were killed 1, 3, 6, 9, 12, 15 and 30 days following a 1-h exposure to 148 mumol 3MF/1. Relatively selective 3MF-induced necrosis of the olfactory epithelium was seen at day 1 post exposure. Subsequent resolution of the acute olfactory necrosis was not complete and resulted in partial occlusive fibrosis of the nasal cavity as seen at 30 days. Pretreatment of the animals with piperonyl butoxide (PB) did not block 3MF-induced olfactory epithelial necrosis although it prevented Clara cell necrosis when given at a dose of 800 mg/kg intraperitoneally 1 h before exposure to 3MF.
Animals↗
Acute inhalation toxicity of 3-methylfuran in the mouse: pathology, cell kinetics, and respiratory rate effects.
The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in male BALB/c mice by morphologic examination of animals killed at varying timepoints following a 1-hr exposure to an initial chamber concentration of 14 to 37 mumol/liter (343 to 906 ppm). In addition, respiratory rate measurements and cell kinetics were used to assess quantitatively pulmonary damage and repair. Necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen 1 day following exposure and was followed by regeneration, which was virtually complete, within 21 days. Cell kinetic studies showed peak bronchiolar cell proliferation at 3 days with a labeling index (LI) of 5.0% compared to 0.4% in controls. An increase in parenchymal cell proliferation was also noted coincident with a mild interstitial pneumonitis. This parenchymal proliferation, peaking at 10 days with an LI of 1.4% compared to 0.2% in controls, consisted primarily of type II epithelial and endothelial cell proliferation indicating possible delayed damage and repair of type I epithelial and endothelial cells. The respiratory rate showed an initial transient increase followed by a more prolonged decrease with eventual return to control levels. 3MF toxicity was also evidenced by a necrotizing suppurative rhinitis, centrilobular hepatic necrosis, lymphocyte necrosis in the thymus and spleen, sialoadenitis, and otitis media.
Air Pollutants↗
The role of toxicological interactions in chemical carcinogenesis.
Toxicological interactions may occur not only when exposure to two or more chemicals is simultaneous, but also when exposures are separated in time. Often the sequence of exposure determines the nature of the toxicological response. This is illustrated with the two hindered phenolic antioxidants, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). Evidence available suggests that in certain tissues exposure to BHT first and then to a carcinogen is without significant consequences, whereas exposure to BHT after a carcinogen may enhance tumor formation. On the other hand, exposure to BHA before carcinogen administration often has a protective effect, whereas exposure to BHA after a carcinogen sometimes protects and sometimes is without any influence. Mechanisms underlying these interactions may be induction of mixed function oxidases, production of cell hyperplasia or other, as yet ill-defined, events such as modification of biological reactivity.
Administration, Oral↗