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Evaluation of the pulmonary effects of HCl using CO2 challenges in guinea pigs.

Pulmonary effects of inhalation exposures to hydrogen chloride were evaluated during and following exposure in male guinea pigs. During exposure, the respiratory rate and the time of onset of sensory or pulmonary irritation as evidenced by the change in respiratory pattern were measured. HCl inhalation resulted in both sensory and pulmonary irritation. The onset of sensory irritation took 6 min during HCl exposures at 320 ppm but less than 1 min at 680, 1040, and 1380 ppm. The onset of pulmonary irritation showed a concentration-response relationship, the higher the concentration the earlier the onset. Following exposure to HCl, animals were evaluated using a pulmonary performance test based on their ventilatory response (respiratory rate and tidal volume) during challenge with 10% CO2. The maximal respiratory frequency achieved during the CO2 challenge was lower in the HCl-exposed animals than in the controls in a HCl concentration-dependent fashion, but HCl had no apparent effect on the maximal tidal volume achieved during CO2 challenges. HCl exposure also affected baseline respiratory rate and tidal volume of the animals after exposure. Impairments of the respiratory function were also supported by evidence of morphological injury in both the airways and the alveolar region.

Animals↗

Chronic pulmonary effects of volcanic ash: an epidemiologic study.

The chronic pulmonary effects of exposure to volcanic ash were investigated by conducting a cross-sectional epidemiological study of 2,006 women between 30 and 59 yr of age who lived in three areas subjected to different levels of airborne ash. In the three areas prevalences of chronic bronchitis and other respiratory symptoms were so low that volcanic ash did not seem to be a major cause of respiratory disease. In the highly exposed area, however, 9.9% of the women experienced symptoms of one or more respiratory diseases, while 6.4% of the women in the medium- and 5.4% of the women in the low-exposure area had these symptoms. Prevalences of each disease and symptom increased as total suspended particulate level increased, suggestive of an association of mild respiratory symptoms with volcanic ash.

Adult↗

Thermodilution versus inert gas rebreathing for estimation of effective pulmonary blood flow.

OBJECTIVE: To compare measurements of the effective pulmonary blood flow (Qep, i.e., nonshunted fraction of cardiac output, Qt) by the inert gas rebreathing (RB) method and the thermodilution (TD) technique in critically ill patients. DESIGN: Prospective, comparative study of a noninvasive method and an established invasive technique. SETTING: An 11-bed general intensive care unit in a university hospital. PATIENTS: A total of 14 critically ill patients, all mechanically ventilated and monitored with systemic and pulmonary artery catheters. MEASUREMENTS AND MAIN RESULTS: Qep was determined in duplicate by RB using a mass spectrometer for gas analysis. For each determination, Qt was measured in triplicate by the cold water bolus TD technique and averaged. Simultaneously mixed venous and arterial blood samples were analyzed to calculate the intrapulmonary shunt fraction and thereby convert estimates of Qt to Qep. Mean difference between paired estimates (RB - TD) was 0.01 L/min, so for differences was 1.19 L/min, and 95% confidence interval for the bias was -0.45 to 0.47 L/min. Coefficients of variation for repeated Qep estimates were 8% (RB) and 12% (TD), respectively. Coefficients of variation for RB estimates of functional residual capacity and lung tissue volume were 6% and 17%, respectively. CONCLUSIONS: The RB method is a promising method for simultaneous noninvasive estimation of Qep and functional residual capacity in mechanically ventilated patients. However, further investigations are needed to evaluate potential problems of the method before it can be recommended for clinical purposes.

Adult↗

Pulmonary effects in man of oral prizidilol hydrochloride (SK&F 92657), a new antihypertensive agent.

The effects on heart rate, blood pressure and pulmonary function of single oral doses of prizidilol hydrochloride (400 mg SK&F 92657) and propranolol (40 mg) were compared with placebo in nine healthy volunteers, in a double blind crossover study. Prizidilol had no effect on heart rate while propranolol caused a significant reduction compared with placebo. Diastolic blood pressure was lowered to the same extent by both prizidilol and propranolol. Propranolol significantly reduced the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the maximal expiratory flow at 50% vital capacity (MEF 50). Prizidilol had no effect on flow-volume loop parameters. Effective pulmonary blood flow was not altered by propranolol, but it was significantly increased by prizidilol. Oral prizidilol exerts its hypotensive effect by vasodilatation without reflex tachycardia. It does not cause airways obstruction in healthy subjects.

Adrenergic beta-Antagonists↗

Comparison of the cardiovascular and pulmonary effects of oral celiprolol, propranolol and placebo in normal volunteers.

1. The effects on heart rate, blood pressure and pulmonary function of single oral doses of celiprolol hydrochloride (400 mg), and propranolol (40 mg) were compared with placebo in 12 healthy volunteers, in a double-blind three-period crossover study. 2. Celiprolol had no effect on heart rate while propranolol caused a significant reduction compared with placebo. Systolic blood pressure was reduced by propranolol but not celiprolol, whereas standing diastolic blood pressure was lowered by both drugs. 3. The maximal expiratory flow at 50% vital capacity (MEF.50), was significantly lower after propranolol compared with placebo and celiprolol. Celiprolol had no effect on the flow-volume loop parameters. 4. Effective pulmonary blood flow was significantly increased by celiprolol, but reduced by propranolol. 5. A high incidence of subjective side-effects were experienced on celiprolol (10/12; particularly unpleasant in 5). Side-effects were experienced to a lesser extent on placebo (8/12). Only one volunteer experienced a side-effect on propranolol. 6. Oral celiprolol exerts its hypotensive effect by vasodilatation without reflex tachycardia. It does not cause airways obstruction in healthy subjects.

Adrenergic beta-Antagonists↗

The influence of sleeping position on functional residual capacity and effective pulmonary blood flow in healthy neonates.

Variation in body position has been shown to affect respiratory function in adults and neonates with and without respiratory illness. At present it remains unclear why respiratory function should be affected by different body positions. We hypothesized that the effect of body weight on the relatively compliant chest wall of the newborn infant in the prone position would cause a reduction in functional residual capacity (FRC) and a compensatory improvement in ventilation/perfusion matching as measured by effective pulmonary blood flow. To evaluate this, a paired crossover study was performed on 12 normal newborn infants. The inert gas (argon) rebreathing method adapted for neonates was used to measure FRC. Simultaneously effective pulmonary blood flow (Qpeff) was determined using Freon 22 and a mass spectrometer with computerized analysis. The babies were studied in three different positions in random order: prone, supine and right lateral decubitus. The means (95% confidence intervals) of the three groups of FRC were 23.8 (19.2 to 28.4), 23.8 (20.2 to 27.5), and 24.3 (19.5 to 29.2) ml/kg, respectively (P = 0.59) and for Qpeff were 104 (91 to 116), 108 (95 to 122), 109 (97 to 122) ml/ kg-min, respectively (P = 0.11). Thus no significant differences were demonstrated. In nine of the babies, a repeat supine measurement was taken at the end of the study to assess repeatability of the method. In these nine babies alone the results were 22.7 (19.1 to 26.3) and 22.1 (18.6 to 25.6) ml/kg for FRC, and 102 (89 to 116) and 98 (90 to 107) ml/kg-min for Qpeff. The coefficients of repeatability were 4.7 ml/kg for FRC (21%) and 30 ml/kg-min for Qpeff (30%).

Argon↗

Pulmonary effects of machining fluids in guinea pigs and mice.

Acute pulmonary effects of inhalation exposure to (unused) neat and in-use metalworking fluids (MWF) were studied to evaluate the potency of characterized MWF in terms of their effects on breathing and lung inflammation. Inhalation exposure of guinea pigs caused dose-dependent changes in respiratory rate and volume that were used to quantify potency. In-use MWF was consistently more toxic than the corresponding neat MWF. Significant predictors of respiratory responses were whether MWF was neat or in-use (p = 0.0001), exposure concentration (p = 0.022), MWF formulation (p = 0.031), and the particular in-use MWF tested (p = 0.032). Inhalation exposures to MWF biocides resulted in dose-dependent sensory irritation responses. Guinea pig studies revealed significant inflammation resulting from MWF exposure marked by change in bronchoalveolar lavage (BAL) fluid from 3% neutrophils (controls) to 60-79% (MWF-exposed) and 25-fold increase in total BAL cells. The in-use MWF ranged in endotoxin concentration from 280 to 1.7 x 10(5) endotoxin units (EU)/mL. To investigate the role of endotoxin, studies were carried out in mice sensitive (SEN) and resistant (RES) to endotoxin. SEN mice revealed a dose-dependent 10,000-fold increase in BAL neutrophils and a 100-fold increased concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) following inhalation exposure to in-use MWF. This inflammatory response was not observed with exposure to neat MWF or with sham exposure. RES mice demonstrated virtually no response to the inhaled MWF for total cells, neutrophils, IL-6, or TNF-alpha. Removal of microorganisms by filtration of the in-use MWF did not change the responses observed in either strain. These studies demonstrate that lung inflammation may be an important outcome from exposure to in-use MWF and that endotoxin is a toxicant of importance.

Acute Disease↗

Pulmonary effects of repeated exposures to paraquat aerosol in guinea pigs.

Exposure to paraquat, a widely used herbicide, has been shown to produce a concentration dependent rapid, shallow breathing pattern in guinea pigs 18 hr following exposure (H. Burleigh-Flayer and Y. Alarie, 1987, Arch. Toxicol. 59(6), 391-396). To further explore the pulmonary effects following exposure to paraquat, two experiments were carried out. The first experiment consisted of exposing a group of guinea pigs for a period of 4 hr to 0.7 mg/m3 paraquat aerosol and monitoring respiratory variables for 2 weeks following the exposure. In the second experiment, three groups of guinea pigs were repeatedly exposed to three concentrations of paraquat aerosol (0.1, 0.4, and 0.8 mg/m3) for 6 hr a day, 5 days a week for 3 weeks. Respiratory variables were measured each day of these 3-week experiments. The respiratory variables evaluated in both experiments were tidal volume (VT) and respiratory frequency (f). These variables were monitored during air breathing and upon challenge with 10% CO2 in 20% O2 and 70% N2 in order to evaluate the pulmonary effects of exposure to paraquat. Following a single exposure to 0.7 mg/m3 paraquat aerosol, a decrease in VT and increase in f were seen during air and 10% CO2 challenge which reached a maximum several days following exposure. After reaching maximal changes, the respiratory variables returned to control values. With repeated 6-hr exposures to paraquat aerosol, guinea pigs exposed to 0.4 and 0.8 mg/m3 also displayed a rapid, shallow breathing pattern. Adaptation to the exposures for these two concentration groups was evidenced by a return of the respiratory variables toward control levels. This adaptation typically occurred during the first 7 days of exposures. A cumulative effect was therefore not detected with repeated exposures to paraquat aerosols.

Aerosols↗

The pulmonary effect of nitric oxide synthase inhibition following endotoxemia in a swine model.

OBJECTIVE: To evaluate the pulmonary effect of treatment with N-nitro-L-arginine methyl ester (NAME) with and without inhaled nitric oxide (NO) in a swine model of endotoxemia. DESIGN: Randomized controlled trial. SETTING: Laboratory. INTERVENTIONS: Following a 20-minute intravenous infusion of Escherichia coli lipopolysaccharide (LPS) (200 micrograms/kg), animals were resuscitated with saline solution (1 mL/kg per minute) and observed for 3 hours while mechanically ventilated (fraction of inspired oxygen [FIO2], 0.6; tidal volume, 12 mL/kg; positive end-expiratory pressure, 5 cm H2O). Group 1 (LPS, n = 6) received no additional treatment; group 2 (NAME, n = 5) received NAME (3 mg/kg per hour) for the last 2 hours; group 3 (NO, n = 6) received NAME (3 mg/kg per hour) and inhaled NO (40 ppm) for the last 2 hours; and group 4 (control, n = 5) received only saline solution without LPS. MAIN OUTCOME MEASURES: Cardiopulmonary variables and blood gases were measured serially. The multiple inert gas elimination technique was performed at 3 hours. The wet-to-dry lung weight ratio was measured following necropsy. RESULTS: Administration of LPS resulted in pulmonary arterial hypertension, pulmonary edema, and hypoxemia with increased ventilation perfusion ratio mismatching. None of these changes were attenuated by NAME treatment alone but all were significantly improved by the simultaneous administration of inhaled NO. CONCLUSIONS: Systemic NO synthase inhibition failed to restore hypoxic pulmonary vasoconstriction following LPS administration. The deleterious effects of endotoxemia on pulmonary function can be improved by inhaled NO but not by systemic inhibition of NO synthase.

Administration, Inhalation↗

Review of pulmonary effects of poly(vinyl chloride) and vinyl chloride exposure.

The contributions of several recent reports to the definition of pulmonary effects of PVC dust inhalation are reviewed. Granulomatous reaction, with inclusion of PVC particles in macrophages and histocytes, and associated interstitial pulmonary fibrosis have been found to lead to exertional dyspnoea, diffuse micronodular chest radiographic opacities and restrictive pulmonary dysfunction. The effects of vinyl chloride (VC) monomer (gas) on proteins and the immunologic mechanisms triggered by the altered protein are possible mechanisms for the development in some cases of interstitial pulmonary fibrosis secondary to VC exposure. Vinyl chloride, a confirmed carcinogen, has been associated with, among other malignant tumors, a significant increase in the incidence of lung cancer. The magnitude of this effect has not yet been completely evaluated.

Dust↗

Myocardial and pulmonary effects of aqueous oxygen with acute hypoxia.

BACKGROUND: The purpose of this paper was to evaluate myocardial and pulmonary effects of aqueous oxygen (AO) delivered directly into the pulmonary circulation in acute hypoxia. METHODS: Six calves (2 months old, 68.0 +/- 2.2 kg) after general anesthesia, mechanical ventilation, and median sternotomy underwent total right heart bypass using fixed flow with continuous pressure and blood gas measurements in carotid and femoral arteries, left atrium, the coronary sinus and PA. Measurements of systemic and PA pressures and O2 saturations; myocardial O2 atrioventricular (AV) differences; and O2 extraction were made. After base line measurements, hypoxic ventilation reducing the mean arterial PO2 from 277 +/- 102 mm Hg to 47 +/- 4 mm Hg (p < 0.0005) was maintained for 30 minutes. Without changes in the hypoxic ventilation (mean arterial PO2 = 49 +/- 11 mm Hg) 3 ml/min of hyperbaric aqueous oxygen (AO = oxygen diluted in saline solution) was administered into the PA for 30 minutes. Pulmonary blood flow was maintained during the entire experiment (3.7 +/- 0.3 L/min). RESULTS: Hypoxic ventilation significantly raised (p < 0.05) the systolic (30 +/- 7 vs 21 +/- 4 mm Hg), diastolic (20 +/- 6 vs 12 +/- 3 mm Hg), and mean (23 +/- 7 vs 15 +/- 3 mm Hg) PA pressure; PA/systemic pressure ratio for systolic (0.37 +/- 0.08 vs 0.25 +/- 0.06) and mean (0.56 +/- 0.19 vs 0.29 +/- 0.11) pressures; and pulmonary vascular resistance (PVR) (5.63 +/- 1.06 vs 3.53 +/- 0.75 U). Aqueous oxygen (AO) infusion significantly reduced (p < 0.05) the values obtained with hypoxic ventilation; systolic (23 +/- 5 vs 30 +/- 7 mm Hg), diastolic (11 +/- 4 vs 20 +/- 6 mm Hg), and mean (14 +/- 3 vs 23 +/- 7 mm Hg) PA pressure; PA/systemic pressure ratio for systolic (0.25 +/- 0.05 vs 0.37 +/- 0.08) and mean pressures (0.29 +/- 0.12 vs 0.56 +/- 0.19); and PVR (3.41 +/- 1.01 vs 5.63 +/- 1.06 U). AO infusion in the pulmonary circulation did not influence the myocardial O2 atrioventricular (AV) difference or the O2 extraction. CONCLUSIONS: Infusion of hyperbaric AO solution into the PA can completely reverse the negative effects of acute hypoxia on the pulmonary circulation without affecting the myocardial metabolism.

Animals↗

Does tachyphylaxis occur to the non-pulmonary effects of salmeterol?

1. The potential for tachyphylaxis to the non-pulmonary effects of salmeterol, a long-acting selective beta 2-adrenoceptor agonist was investigated in 12 healthy male subjects in a double-blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12-lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2-adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

Pulmonary effects of exposures in silicon carbide manufacturing.

Chest x rays, smoking histories, and pulmonary function tests were obtained for 171 men employed in the manufacturing of silicon carbide. A lifetime exposure to respirable particulates (organic and inorganic fractions) and sulphur dioxide was estimated for each worker. Chest x ray abnormalities were related to respirable particulates (round opacities) and to age and smoking (linear opacities). Pulmonary function was affected by respirable particulates (FVC) and by sulphur dioxide and smoking (FEV1). Pleural thickening was related to age. No exposures exceeded the relevant standards; we therefore conclude that the current standards do not provide protection against injurious pulmonary effects, at least in this industry.

Adult↗

Pulmonary effects of fixation of a fracture with a plate compared with intramedullary nailing. A canine model of fat embolism and fracture fixation.

UNLABELLED: Fat-embolism syndrome and pulmonary dysfunction may develop in multiply injured patients who have a fracture of a long bone. Although early fixation of a fracture is beneficial, intramedullary nailing may exacerbate pulmonary dysfunction by causing additional embolization of marrow fat. We examined the pulmonary effects of the timing and method of fixation of a fracture in a canine fat-embolism model. Fat embolism was induced in forty-one adult dogs by reaming the ipsilateral femur and tibia followed by pressurization of the intramedullary canal. The animals were divided into a control group of eight dogs that had induction of fat embolism alone and an experimental group of thirty-three dogs that had induction of fat embolism and internal fixation of a transverse fracture of the middle of the contralateral femoral shaft. In the control group, four dogs each were killed four hours and twenty-four hours after induction of fat embolism. In the experimental group, a femoral fracture was created and fixation was performed four hours after embolic showering in fifteen animals and twenty-four hours after embolization in eighteen animals. The two experimental groups were subdivided according to the method of fixation of the fracture: eleven dogs each had application of a plate, nailing without reaming, and nailing with reaming. The pulmonary arterial pressure and the alveolar-arterial gradient were measured preoperatively, during induction of fat embolism, and as long as one hour after fixation of the fracture but before the animal was killed. The lungs, brain, and kidneys were examined for pathological and physiological evidence of intravascular fat. The intravascular fat persisted for twenty-four hours after induction of pulmonary fat embolism. Pulmonary arterial pressure remained elevated at four hours after the embolic showering, before creation and fixation of the fracture. By twenty-four hours after the induction of fat embolism, pulmonary arterial pressure had returned to the baseline level. Neither the creation nor the fixation of the fracture affected pulmonary arterial pressure. In the animals that had fixation of a fracture four hours after embolization, both nailing with reaming and nailing without reaming produced alveolar-arterial gradients that were higher than the baseline values, whereas fixation with a plate did not change the alveolar-arterial gradient significantly from the baseline value. In addition, the alveolar-arterial gradients in the animals that had nailing with reaming and nailing without reaming four hours after embolization were, respectively, four and 3.5 times higher than that in the animals that had fixation of the femur with a plate. In the animals that had fixation twenty-four hours after embolization, none of the methods for fixation affected the alveolar-arterial gradient. The amount of embolic fat in the lungs, brain, and kidneys was not affected by fixation of the fracture when it was performed at either the four-hour or the twenty-four-hour time-interval. Scores for pulmonary edema were increased by fixation of the fracture, but there was no difference among the scores associated with the three methods of fixation. CLINICAL RELEVANCE: The findings of the present study indicated that the amount of intravascular fat persisting in the lungs, kidneys, and brain twenty-four hours after pressurization of the intramedullary canal is not affected by the method of fixation of the fracture. Fixation of a fracture is associated with minimum evidence of acute inflammation and has no effect on pulmonary artery pressure. The development of pulmonary dysfunction from fat emboli depends on other factors, not just on the presence of fat in pulmonary vessels. It appears that the method of fracture fixation has little influence on the outcome of treatment.

Animals↗

The effect of lung burden on biopersistence and pulmonary effects in rats exposed to potassium octatitanate whiskers by inhalation.

The effect of lung burden on biopersistence and histopathological changes caused by potassium octatitanate whiskers (POW) which is one of the asbestos substitutes were investigated for 1-yr and 4-wk inhalation periods. In the 1-yr inhalation experiment, male Wistar rats were exposed to POW (TW) for 6 h/d, 5 d/wk under the same conditions as a previous study of POW (PT1, JFM fiber) which is made by different manufacturer. The exposure concentration was 1.9 +/- 0.7 mg/m(3) and the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) in the chamber were 1.6 microm and 2.9. Rats were sacrificed at 3 d and 1 yr after the inhalation experiment and TW deposits in the lungs were determined by ICP-AES. Lung burden at 3 d and 1 yr after the inhalation was 2.39 +/- 0.50 mg and 1.37 +/- 0.96 mg, respectively, the deposition fraction was 8.1% and biological half time (BHT) was 15 months. Aggregated dust cells and mild fibrotic changes around these dust cells were observed in the exposed rat lung. These results were almost the same as those obtained in the previous 1-yr PT1 study. In the 4-wk inhalation experiment, to investigate the effect of lung burden on biopersistence and histopathological change, male Wistar rats were exposed to PT1. The exposure concentration was 102 +/- 21 mg/m(3), MMAD (GSD), the geometiric mean length and diameter (GSD) of the PT1 in the chamber were 1.6 microm (3.0), 2.2 microm (1.8) and 0.33 microm (1.5), respectively. Rats were sacrificed at 3 d, 1 wk, and 1, 3, 6 and 12 months after the inhalation experiment. The lung burden of POW at 3 d after 4 wk inhalation was 1.49 +/- 0.19 mg, which was close to the estimated amount of overload. The BHT of the total mass (4.1 months) was not prolonged, but aggregated dust cells were observed in the subpleural region and around the bronchioles and mild fibrotic changes were observed only around the dust cells at one year after the 4-wk inhalation. It is considered that the excessive exposure which impairs the function of alveolar macrophage mediated clearance may cause the aggregation of dust cells and fibrotic changes.

Animals↗

The effect of lung burden on biopersistence and pulmonary effects in rats exposed to potassium octatitanate whiskers by intratracheal instillation.

In our previous inhalation studies on health effects of the asbestos substitute, potassium octatitanate whiskers (POW), we showed that an excess amount of POW deposition in the rat lung increased biopersistence resulting in fibrotic changes. The critical deposition amount which induced the higher biopersistence was estimated to lie between 1.5 mg and 2.4 mg. In order to find the exact amount, the relationship between the lung POW burden and biopersistence was investigated by the intratracheal instillation method. The chemical formula of POW is K2Ti8O17 and the geometric mean fiber diameter (geometric standard deviation, GSD) and geometric mean fiber length (GSD) are 0.35 microm (1.6) and 4.4 microm (2.7), respectively. Rats were intratracheally instilled with 0.5 mg, 1.0 mg, 2.0 mg or 5.0 mg of POW and sacrificed at 1 day and 1, 3, 6 and 12 months after the instillation. The POW amount in each lung was chemically analyzed by ICP-AES after microwave digestion and the biological half time (BHT) of each POW dose was calculated. The BHTs of each group were 10, 15, 20 and 42 months for 0.5, 1.0, 2.0 and 5.0 mg of POW, respectively, and BHT showed a linear dose-dependent increase, but without a threshold within the range of 0.5 mg to 5.0 mg, which was recognized in our earlier inhalation studies. In the histopathological photograph just after the instillation, many macrophages, which had phagocytized many more fibers, existed around the bronchiole compared with the earlier inhalation study at almost the same deposited amount. The relationship between POW amount and biopersistence in this intratracheal instillation study was different from that of our previous inhalation studies, probably due to the unnatural method of the fiber introduction to the lung, which in turn led to a different fiber distribution. It is suggested that an intratracheal instillation study is not an appropriate method for estimating excess deposition amounts of POW and an inhalation study will be needed. However, this intratracheal instillation study clarified that the clearance of POW was delayed as compared with previous inhalation studies at similar deposition amounts and this result has importance for the hazard assessment of dusts in animal experiments.

Animals↗