A dose-response model for refractory ceramic fibers

Refractory ceramic fibers (RCFs) are man-made vitreous fibers commonly used in insulation applications above 1000 degrees C. Although they have been subjected to considerable toxicologic evaluation, only the pooled results from two rat inhalation studies provide data that may be suitable for performing a numerical risk assessment. Even in these inhalation studies, good evidence exists that the maximum tolerated dose (MTD) was exceeded and that pulmonary overload occurred, a condition that will cause tumors whatever the dust responsible. Indeed, a significant yield of tumors was only obtained at the highest dose tested. If these results are omitted, there is no statistically significant evidence of carcinogenicity within the RCF results. Although there is little evidence that overload-related tumors are relevant to human risk, we adopted a conservative approach to obtain the estimates of risk regardless of overload, using a biologically based model, the two-stage clonal expansion model, as well as various statistical models, including the benchmark dose model. We argue that the data favor the use of a biologically based model, which gives the best fit when the highest dose RCF exposures are omitted. Continuing with this model, we show that available data from the RCF experiment, less outliers, coupled with results from other experiments with man-made mineral fibers (MMVFs), demonstrate that all MMVFs are potentially carcinogenic, with any risk mediated by the fibers' biopersistence. Application of this "all MMVF data set" model yields a maximum likely estimate for RCF excess unit risk of 4.6 x 10(-5) (95% upper confidence limit = 9.2 x 10(-5) per fiber/ml). This implies that the risk from occupational exposure to RCFs at 1 fiber/ml for a typical working lifetime would not exceed 10(-4).     

Selected responses of hypertension-sensitive and resistant rats to inhaled acrolein

The Dahl selected rat lines, one susceptible to salt-induced hypertension (DS) and the other resistant to salt-induced hypertension (DR), were exposed to filtered air, 0.4, 1.4, or 4.0 ppm acrolein for 6 h/day, 5 days/week for 62 days. All of the DS rats exposed to 4.0 ppm acrolein died within the first 11 days, while 60% of the DR animals survived the duration of the study. Neither dose dependent blood pressure changes nor altered behavioral characteristics were evident in either rat strain following acrolein exposure. Exposure to 4.0 ppm acrolein increased the level of several serum enzymes in the DR rats which survived. This concentration of acrolein also led to pulmonary edema and a significant increase in lung connective tissue in these animals. There was a marked difference in the pulmonary pathology observed in DS and DR rats exposed to 4.0 ppm acrolein. The lungs of moribund DS rats exhibited severe airway epithelial necrosis with edema and hemorrhage, while surviving DR rats primarily showed a proliferative change. Following exposure to 0.4 and 1.4 ppm acrolein, both rat lines displayed similar pathologic changes. Epithelial hyperplasia and/or clusters of macrophages were usually found near terminal bronchiolar areas. These findings suggest that further investigation of the physiopathologic sensitivity of the DS rat line may elucidate a model for investigating the underlying characteristics of stress susceptible populations.     

Pulmonary response to inhaled Kevlar aramid synthetic fibers in rats

Groups of male rats were exposed to specially prepared ultrafine Kevlar pulp fibers (du Pont's registered trademark for certain aramid fibers) at atmospheric concentrations of either 0.1, 0.5, 3.0, or 18 mg/m3 for 2 weeks. Rats were killed at 0 and 2 weeks and 3 and 6 months postexposure (PE) except the rats exposed to 18 mg/m3, which were killed 0, 4, and 14 days and 1, 3, and 6 months PE. Another group of male rats was exposed to 18 mg/m3 (respirable dust approximately 2.5 mg/m3) of commercial Kevlar fibers for 2 weeks and were killed at 0 and 2 weeks and 3 and 6 months PE. Inhaled ultrafine Kevlar fibers were mostly phagocytized by alveolar macrophages (dust cells) in the alveolar ducts and adjoining alveoli after exposure to either 0.1 or 0.5 micrograms/m3. Most dust cells had disappeared and lungs showed a normal appearance throughout 6 months PE. The pulmonary response almost satisfied the biological criteria for a nuisance dust. Rats exposed to 3 mg/m3 ultrafine Kevlar fibers revealed occasional patchy thickening of alveolar ducts with dust cells and inflammatory cells but with no collagen fibers deposited throughout 6 months PE. After exposure to 18 mg/m3 ultrafine Kevlar, the respiratory bronchioles, alveolar ducts, and adjoining alveoli showed granulomatous lesions with dust cells by 2 weeks PE. The granulomatous lesions converted to patchy fibrotic thickening with dust cells after 1 month PE. The fibrotic lesions were markedly reduced in cellularity, size, and numbers from 3 to 6 months PE but revealed networks of reticulum fibers with slight collagen fiber deposition.     

The influence of refractory ceramic fibres on pulmonary morphology, redox and immune system in rats

Refractory ceramic fibres (RCF) were studied in male SPRD rats by both in vivo long term sequential and in vitro methods. RCF was administered by single intratracheal instillation and the lungs were examined at the end of months 1, 3 and 6 after exposure. In addition, the direct toxicity of the fibres was examined in a primary culture of alveolar macrophages (AM) and in pneumocytes type II (T2). Pulmonary morphological changes, a number of parameters of the redox system, such as activity of extracellular Cu,Zn/superoxide dismutase (EC-SOD), total glutathione content of the lungs (GSH) and immunoglobulins in bronchoalveolar lavage (IgA, IgG, IgM) and in the blood were measured. The composition of the original RCF and the elemental content of the lung tissue were compared by energy dispersive x-ray analysis (EDXA) before and after exposure. Macrophage alveolitis became confluent and moderate fibrosis developed by the end of month 3, and after 6 months of exposure the intensity decreased to the level of the first month. The RCF did not significantly influence the activity of EC-SOD or the total glutathione content of the lungs. Although aluminium and silicon could be demonstrated by EDXA in the lung tissue at the end of month 3, these elements were no longer detectable by the end of month 6. The RCF decreased IgA significantly in bronchoalveolar lavage (BAL). The main components of RCF induced pulmonary alterations, whereas no significant change could be detected in EC-SOD and GSH. Injuries caused by direct toxicity could be observed in the cell membranes only at the highest concentration. On the basis of these results RCF can be determined as moderately toxic fibres.     

Comparison of acute ozone-induced nasal and pulmonary inflammatory responses in rats

The centriacinar pulmonary lesion induced by ozone has been extensively characterized, but little is known about the effects of this oxidant gas in the upper airways. The present study was designed to compare the effects of acute ozone exposure in the nose and lungs of rats. We examined the cellular inflammatory responses in the nasal cavity and lower respiratory tract by means of nasal and bronchoalveolar lavage and morphometric quantitation of neutrophils within the nasal mucosa and pulmonary terminal bronchioloalveolar duct regions (i.e., centriacinar). Rats were exposed to 0.0, 0.12, 0.8, or 1.5 ppm ozone for 6 hr and were sacrificed immediately or 3, 18, 42, or 66 hr following exposure. Eighteen hours after exposure, increased numbers of neutrophils, as compared to controls, were recovered from nasal lavage fluid (NLF) of rats exposed to 0.12 ppm ozone. There was no change in the number of neutrophils recovered from bronchoalveolar lavage fluid (BALF) at any time after exposure. Rats exposed to 0.8 ppm ozone had more neutrophils in NLF than controls immediately after exposure, but no concomitant increase in BALF neutrophils at that time. However, as the number of neutrophils in BALF increased (maximum at 42 hr), the number of neutrophils recovered from NLF decreased (minimum at 42 hr). Rats exposed to 1.5 ppm ozone had no significant increases in nasal neutrophils in NLF at any time after exposure but had greatly increased numbers of neutrophils in BALF 3, 18, and 42 hr after exposure. The number of neutrophils recovered by nasal and bronchoalveolar lavage accurately reflected the tissue neutrophil response at sites within the nasal cavity and lung that were injured by acute ozone exposure. Our results suggest that at high ozone concentrations (0.8 and 1.5 ppm), the acute nasal inflammatory response is attenuated by a simultaneous, competing, inflammatory response within the centriacinar region of the lung. Analysis of nasal lavage fluid for changes in cellular composition may be a useful indicator of acute exposure to ambient levels of ozone, but at higher ozone levels, the nasal cellular inflammatory response may underestimate the effects of ozone on nasal and pulmonary epithelia.     

Enhanced pulmonary inflammatory response to inhaled endotoxin in pregnant rats

Evidence suggests that pregnant animals are more sensitive than nonpregnant animals to the systemic administration of endotoxin. Studies were undertaken to assess whether an enhanced sensitivity of the pulmonary system to aerosolized endotoxin might exist during pregnancy. Pregnant Sprague-Dawley female rats (17 d of gestation) or age-matched virgin female rats were exposed to air or endotoxin (lipopolysaccharide) by inhalation for 3 h. At 18 h following exposure to endotoxin, lactate dehydrogenase activity levels in bronchoalveolar lavage (BAL) fluid samples from pregnant rats were 1.5-fold greater than those from endotoxin-exposed virgin rats. BAL polymorphonuclear leukocyte (PMN) numbers were also approximately twofold greater in pregnant rats than in virgins following the inhalation of endotoxin. The increases in BAL PMNs in pregnant rats following endotoxin exposure were observed just following exposure to endotoxin as well as at 18 h following exposure. These results indicate that an increased pulmonary inflammatory response to inhaled endotoxin occurs during pregnancy in rats. Additional findings suggest that these pregnancy-linked pulmonary responses to endotoxin cannot be explained by the following potential mechanisms: changes in the inhaled dose of endotoxin, or alterations in the responsiveness of alveolar macrophages to endotoxin. To our knowledge this is the first study that has evaluated pulmonary responses to inhaled endotoxin during pregnancy. Our finding that pregnancy is associated with an increased lung inflammatory response to aerosolized endotoxin raises the possibility that there may be a generalized enhancement of pulmonary responses to inhaled toxic agents during pregnancy.     

Surface reactivity,cytotoxicity, and transforming potency of iron-covered compared to untreated refractory ceramic fibers

Untreated and iron-coated refractory ceramic fibers (RCFs) 1, 3, and 4 were examined for their potential to generate free radicals and to catalyze hydrogen peroxide decomposition in cell-free assays and were compared for cytotoxic and transforming potencies in Syrian hamster embryo (SHE) cell system. Coating with a high quantity of iron increased the capability of RCFs to generate hydroxyl radicals and to catalyze the decomposition of hydrogen peroxide. In the SHE cells, the untreated RCFs had varying ability to induce inhibition of cell proliferation, cytotoxicity (as measured by the colony-forming efficiency, CE) and morphological transformation, in a concentration-dependent manner. According to cytotoxic and transforming potencies, they ranged as follows: RCF3 > RCF1 > RCF4. The lethal concentration 50 (LC50; decrease of CE to 50% of controls after 7 d of treatment) expressed per number of RCF3 and RCF1/cm(2) of culture dish was 2.5 x 10(4) and 3.7 x 10(4), respectively, whereas RCF4 was not cytotoxic up to the highest concentration tested (23.7 x 10(4) fibers/cm(2)). At LC50, RCF3 was 1.4-fold more transforming than RCF1, and the weakest, RCF4, induced less than 1% transformation. Iron coating of RCF1 and RCF3 markedly attenuated their cytostatic, cytotoxic, and transforming potencies without a linear concentration-transformation relationship. In contrast, iron coating of RCF4 affected slightly its low transforming potency, although the growth inhibitory effect was reduced. The observed decrease rather than increase in the cytotoxic and transforming potencies of the active samples RCF1 and RCF3 by their coating with large amounts of ferric iron suggests that it is not the quantity or any form of iron on the surface of fibers but the iron, even in trace, in a particular redox and coordinate state that might play a role in the fiber's surface reactivity with regard to the biological material. Surface chemical functions involved in the interaction with the cell could be inactivated by the deposition of a high quantity of Fe(III) on the surface of fibers. Physicochemical studies correlated to biological effects is an approach for understanding the properties of solids related to a given biological response and for elucidating the cellular and molecular mechanisms.     

Cardiovascular responses in unrestrained WKY rats to inhaled ultrafine carbon particles

Based on epidemiologic observations, the issue of adverse health effects of inhaled ultrafine particles (UFP) is currently under intensive discussion. We therefore examined cardiovascular effects of UFP in a controlled animal exposure on young, healthy WKY rats. Short-term exposure (24 h) to carbon UFPs (38 nm, 180 microg m (-3)), generated by spark discharging, induced a mild but consistent increase in heart rate (18 bpm, 4.8%), which was associated with a significant decrease in heart-rate variability during particle inhalation. The timing and the transient character of these responses point to a particle induced alteration of cardiac autonomic balance, mediated by a pulmonary receptor activation. After 24 h of inhalation exposure, bronchoalveolar lavage revealed significant but low-grade pulmonary inflammation (clean air 1.9% vs. UFPs 6.9% polymorphonuclear cells) and on histopathology sporadic accumulation of particle-laden macrophages was found in the alveolar region. There was no evidence of an inflammation-mediated increase in blood coagulability, as UFP inhalation did not induce any significant changes in plasma fibrinogen or factor VIIa levels and there were no prothrombotic changes in the lung or the heart at both the protein and mRNA level. Histological analysis revealed no signs of cardiac inflammation or cardiomyopathy. This study therefore provides toxicological evidence for UFP-associated pulmonary and cardiac effects in healthy rats. Our findings suggest that the observed changes are mediated by an altered sympatho-vagal balance in response to UFP inhalation, but do not support the concept of an inflammation-mediated prothrombotic state by UFP.     

Effects of inhaled glaucine on pulmonary responses to antigen in sensitized guinea pigs

The alkaloid (S)-(+)-1,2,9,10-tetramethoxyaporphine (glaucine) is a phosphodiesterase 4 inhibitor with bronchodilator and anti-inflammatory activity in vitro. In this study, we examined the in vivo effects of glaucine on an animal model of asthma. In ovalbumin sensitized guinea pigs, inhaled glaucine (10 mg ml(-1), 3 min) inhibited the acute bronchoconstriction produced by aerosol antigen (antigen response was 256+/-42 and 95+/-14 cm H(2)O l(-1) s(-1) in control and glaucine-treated animals, respectively; P<0.05). Pretreatment with glaucine (10 mg ml(-1), 10 min inhalation, 30 min pre- and 3 h post-antigen exposure) markedly reduced airway hyperreactivity to histamine, eosinophil lung accumulation, and increased eosinophil peroxidase activity in bronchoalveolar lavage fluid 24 h after exposure of conscious guinea pigs to aerosol antigen. In addition, inhaled glaucine (5-10 mg ml(-1), 3 min) inhibited the microvascular leakage produced after inhaled antigen at all airway levels. These data support the potential interest of phosphodiesterase 4 inhibitors in asthma treatment.     

Effects of inhaled ozone on pulmonary immune cells critical to antibacterial responses in situ

The goal of this study was to examine effects from repeated exposure to ozone (O3) on immune cells involved in cell-mediated antibacterial responses in the lungs. Rats exposed to 0.1 or 0.3 ppm O3 for 4 h/day, 5 days/wk, for 1 or 3 wk were analyzed for the ability to clear an intrapulmonary challenge with Listeria monocytogenes or had their lungs processed to obtain pulmonary alveolar macrophages (PAM) and lung-associated lymphocytes for analyses of select cell functions and surface marker expression. The results indicate that repeated inhalation exposure to O3 affected local cell-mediated immunity (CMI) responses as evidenced by effects on clearance of Listeria. However, this modulation was not consistently dependent on exposure concentration or duration. Short-term repeat exposures had more effect on host resistance than did the more prolonged regimen, with rats exposed to 0.1 ppm O3 most adversely impacted. Clearance patterns suggest modifications in innate resistance following 1 wk of exposure to 0.1 ppm O3, but no similar effect following a 3-wk regimen. Exposure to 0.3 ppm O3 appeared to affect both innate and acquired resistance after a 1-wk regimen, but mainly the former after an additional 2 wk of exposure. We conclude that these two mechanisms of resistance are differentially affected by O3 and that distinct time- and O3 concentration-dependent adaptation phenomena evolve for each; that is, in situ adaptation to higher levels of O3 may occur more readily with acquired than with innate/PAM-dependent resistance. A similar pattern of inconsistent effect on PAM and lung-associated lymphocytes was also evident. For example, while 3-wk exposures had a greater effect on PAM reactive oxygen intermediate ROI production, evidence for a significant effect on antibacterial activity was only notable among PAM from rats exposed for 1 wk. Among lung lymphocytes, while 3-wk exposure to 0.1 ppm O3 led to a significant increase in CD25 expression, there was no corresponding increase in responsivity to concanavalin A (ConA); only among cells from 1-wk-exposed rats did lymphoproliferative responses increase. Though investigations of altered immune cell cytokine receptor expression/binding activity are ongoing, results herein provide further evidence to support our longstanding hypothesis that some well-documented effects of O3 exposure on human health are quite likely linked to changes in local immune cell (i.e., PAM and lung-associated lymphocytes) functions, with the latter being related to changes in the capacities of these cells to interact with immunoregulatory cytokines.     

三种血管舒张剂对慢性缺氧性肺动脉高压大鼠肺动脉收缩反应的比较

观察了米力农(Mil), lemakalim (Lem)和维拉帕米(Ver)三种血管舒张剂对前列腺素F_2α (PGF_2α)所致缺氧2和4 wk大鼠肺动脉和主动脉环收缩反应的影响. Lem (0.01～1.0 μmol·L^-1), Mil和Ver(均为0.1～10.0 μmol·L^-1)对主动脉和肺动脉都有明显的抑制作用, 使PGF_2α引起的血管收缩反应曲线压低, EC₅₀显著增高(P<0.001), 呈剂量相关关系. 其抑制强度为Lem>Mil>Ver, 缺氧前后顺序不变. 无论缺氧前后, Lem和Ver对主动脉和肺动脉的抑制强度都较接近, Mil则在缺氧条件?下, 对肺动脉的抑制作用选择性地增强.     

三种血管舒张剂对慢性缺氧性肺动脉高压大鼠肺动脉收缩反应的比较

观察了米力农（Ｍｉｌ），ｌｅｍａｋａｌｉｍ（Ｌｅｍ）和维拉帕米（Ｖｅｒ）三种血管舒张剂对前列腺素Ｆ２α（ＰＧＦ２α）所致缺氧２和４ｗｋ大鼠肺动脉和主动脉环收缩反应的影响．Ｌｅｍ（０．０１～１．０μｍｏｌ·Ｌ－１），Ｍｉｌ和Ｖｅｒ（均为０．１～１０．０μｍｏｌ·Ｌ－１）对主动脉和肺动脉都有明显的抑制作用，使ＰＧＦ２α引起的血管收缩反应曲线压低，ＥＣ５０显著增高（Ｐ＜０．００１），呈剂量相关关系．其抑制强度为Ｌｅｍ＞Ｍｉｌ＞Ｖｅｒ，缺氧前后顺序不变．无论缺氧前后，Ｌｅｍ和Ｖｅｒ对主动脉和肺动脉的抑制强度都较接近，Ｍｉｌ则在缺氧条件下，对肺动脉的抑制作用选择性地增强     

Perspectives on refractory ceramic fiber (RCF) carcinogenicity: comparisons with other fibers

Abstract

In 2011, SCOEL classified RCF as a secondary genotoxic carcinogen and supported a practical threshold. Inflammation was considered the predominant manifestation of RCF toxicity. Intrapleural and intraperitoneal implantation induced mesotheliomas and sarcomas in laboratory animals. Chronic nose-only inhalation bioassays indicated that RCF exposure in rats increased the incidence of lung cancer and similar exposures resulted in mesothelioma in hamsters, but these studies may have been compromised by overload. Epidemiological studies in the US and Europe showed an association between exposure and prevalence of respiratory symptoms and pleural plaques, but no interstitial fibrosis, mesotheliomas, or increased numbers of lung tumors were observed. As the latency of asbestos induced mesotheliomas can be up to 50 years, the relationship between RCF exposure and respiratory malignances has not been fully determined. Nonetheless, it is possible to offer useful perspectives. RCF and rock wool have similar airborne fiber dimensions and biopersistence. Therefore, it is likely that these fibers have similar toxicology. Traditional rock wool has been the subject of numerous cohort and case control studies. For rock wool, IARC () concluded that the epidemiological studies did not provide evidence of carcinogenicity. Based on analogies with rock wool (read across), it is reasonable to believe that increases in lung cancer or any mesotheliomas are unlikely to be found in the RCF-exposed cohort. RCF producers have developed a product stewardship program to measure and control fiber concentrations and to further understand the health status of their workers.     

Ventilatory responses of dystrophic and control hamsters to naloxone

In this study we determined if endogenous opioid peptides may contribute to the depression of ventilation seen in dystrophic hamsters. Ventilation of control and dystrophic awake hamsters was determined prior to either naloxone (1 mg/kg) or saline administration and then 5, 15 and 30 minutes postinjection. Subsequently, animals were exposed to a hypercapnic challenge (7% CO2 in O2). Control hamsters increased ventilation significantly (p less than 0.01) after naloxone compared to saline treatment. In contrast, dystrophic hamsters showed no difference in ventilation when they received either naloxone or saline. Both groups increased ventilation significantly (p less than 0.05) after hypercapnic challenge, whether they had received naloxone or saline. Although dystrophic hamsters can respond to a ventilatory stimulant (CO2), naloxone did not increase ventilation, possibly indicating that endogenous opioids are not responsible for their depressed ventilation.     

Development of a short-term inhalation bioassay to assess pulmonary toxicity of inhaled particles: comparisons of pulmonary responses to carbonyl iron and silica.

This paper describes a short-term inhalation bioassay for evaluating the lung toxicity of inhaled particulate materials. To validate the method, rats were exposed for 6 hr or 3 days to various concentrations of either aerosolized alpha-quartz silica or carbonyl iron particles. Cells and fluids from groups of sham- and dust-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase (LDH), and protein values were measured in BAL fluids at several time points postexposure. Cells were identified, counted, and evaluated for viability. Pulmonary macrophages (PM) were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy. The lungs of additional exposed animals were processed for histopathology and transmission electron microscopy. Brief exposures to silica elicited a sustained granulocytic inflammatory response (primarily neutrophils) with concomitant increases in alkaline phosphatase, LDH, and protein in the lavage fluids (p less than 0.05). In addition, PM functional capacity was depressed (p less than 0.05) and histopathologic lesions were observed within 1 month after exposure. In contrast, 6-hr or 3-day exposures to CI produced no cellular, cytotoxic, or alveolar/capillary membrane permeability changes at any time postexposure. PM function was either enhanced or unchanged from controls. These data demonstrate that short-term, high-dose inhalation exposures of silica produce effects similar to those previously observed using intratracheal instillation or chronic inhalation models, and lend support to this method as a reliable short-term bioassay for evaluating the pulmonary toxicity and mechanisms associated with exposures to new and untested materials.     

Comparison of hypokalaemic,electrocardiographic and haemodynamic responses to inhaled isoprenaline and salbutamol in young and elderly subjects

Summary The purpose of the study was to compare beta-adrenoceptor responsiveness to salbutamol (beta-₂ selective agonist) and isoprenaline (non-selective) in young (n=10, age 23 y) and elderly (n=7, age 71 y) subjects. Subjects were given cumulative doubling doses of inhaled isoprenaline or salbutamol (500–4000 g), and placebo, in a single-blind randomised cross-over design. Plasma potassium, electrocardiographic (R-R, T-wave, Q-Tc) and blood pressure responses were measured at baseline and at each dose step.There were no difference between baseline values for each of the three study days within each group of subjects. Hypokalaemia was significantly greater in response to salbutamol compared with isoprenaline in both the young (as change from baseline): –0.61 versus –0.10 mmol·1^–1; and in the elderly: –0.68 versus –0.20 mmol·1^–1. There were no differences between young and elderly responses. T-wave amplitude fell significantly in repsonse to isoprenaline and salbutamol, although this effect was progressively attenuated with increasing doses of isoprenaline. Maximum T-wave response (change from baseline) was greater with salbutamol than isoprenaline in the young: –0.22 versus –0.11 mV; and in the elderly: –0.17 versus –0.08 mV, and there were no differences between the two groups.There were no differences between the effects of isoprenaline and salbutamol on Q-Tc prolongation or heart rate. Chronotropic responses to salbutamol were greater in the elderly: 39 versus 24 beats·min^–1. There were larger increases in SBP with isoprenaline in both groups. Falls in DBP in response to isoprenaline and salbutamol were significantly greater in the elderly.These findings suggest that inhaled isoprenaline is a less potent stimulant of extrapulmonary beta-₂ adrenoceptors compared with salbutamol, but has a greater effect on cardiac beta-₁ adrenoceptors. There was no evidence of a decline with ageing in the function of beta-₁ or beta-₂ adrenoceptors.     

Pleural dosimetry and pathobiological responses in rats and hamsters exposed subchronically to MMVF 10a fiberglass.

Interspecies differences in pulmonary and pleural responses to the inhalation of natural mineral and synthetic vitreous fibers have been observed in chronic and subchronic studies. However, the reasons for these differences are not clearly understood. There are also fiber-specific differences in the outcome of chronic inhalation exposure to natural mineral and synthetic vitreous fibers. Whether these differences are dependent upon the ability of these fibers to translocate to the pleural space is unknown. The present study was conducted to compare retained fiber burdens and selected pathological responses in the pleural compartments of rats and hamsters following subchronic inhalation of MMVF 10a fiberglass, a fiber negative for tumorigenesis or fibrosis in chronic studies. Fischer 344 rats and Syrian golden hamsters were exposed for 4 or 12 weeks by nose-only inhalation at nominal aerosol mass concentrations of 45 mg/m3 (610 WHO fibers/cc). Pulmonary fiber burdens and pulmonary inflammatory responses were greater in rats than in hamsters. The total number of fibers in the lung was approximately three orders of magnitude greater than in the pleural compartment. Pleural burdens in the hamster (160 fibers/cm2 surface area) were significantly greater than burdens in similarly exposed rats (60 fibers/cm2 surface area) following 12 weeks of exposure. With time postexposure, pleural burdens decreased in hamsters but were essentially unchanged in rats. Pleural inflammatory responses in both species were minimal. In rats, pleural inflammation was characterized by increased numbers of macrophages and increases in mesothelial cell replication during the period of fiber exposure. In contrast, hamsters had increased numbers of macrophages and lymphocytes, and mesothelial-cell replication indices were elevated on the parietal pleura of the costal wall and diaphragm, with some of these responses persisting through 12 weeks of postexposure recovery. Taken together, the results suggest that differences among rodent species in pleural responses to inhaled fibers are due to a delivered dose of fibers and to the biological responses to the presence of the fibers.     

Characterization of pulmonary responses in mice to asbestos/asbestiform fibers using gene expression profiles

Humans exposed to asbestos and/or asbestiform fibers are at high risk of developing many lung diseases including asbestosis, lung cancer, and malignant mesothelioma. However, the disease-causing potential and specific metabolic mechanisms and pathways associated with various asbestos/asbestiform fiber exposures triggering different carcinogenic and non-carcinogenic outcomes are still largely unknown. The aim of this this study was to investigate gene expression profiles and inflammatory responses to different asbestos/asbestiform fibers at the acute/sub-acute phase that may be related to delayed pathological outcomes observed at later time points. Mice were exposed to asbestos (crocidolite, tremolite asbestos), asbestiform fibers (erionite), and a low pathogenicity mineral fiber (wollastonite) using oropharyngeal aspiration. Similarities in inflammatory and tissue damage responses, albeit with quantitative differences, were observed at day 1 and 7 post treatment. Exposure to different fibers induced significant changes in regulation and release of a number of inflammatory cytokines/chemokines. Comparative analysis of changes in gene regulation in the lung on day 7 post exposure were interpretable in the context of differential biological responses that were consistent with histopathological findings at days 7 and 56 post treatment. Our results noted differences in the magnitudes of pulmonary responses and gene regulation consistent with pathological alterations induced by exposures to four asbestos/asbestiform fibers examined. Further comparative mechanistic studies linking early responses with the long-term endpoints may be instrumental to understanding triggering mechanisms underlying pulmonary carcinogenesis, that is lung cancer versus mesothelioma.     

Interspecies comparisons of lung responses to inhaled particles and gases

Two important challenges for inhalation toxicologists involve the elucidation of mechanisms of lung toxicity caused by inhalation of chemicals or particulate materials, as well as the extrapolation of animal data to humans. Because risk estimates of toxicity generally are dependent upon experimental data for which a variety of species are utilized, a fundamental knowledge of species similarities and differences in lung anatomy, physiology, biochemistry, cell biology, and corresponding disease processes is essential. In the present review, the known mechanisms of particle deposition and clearance among various species have been highlighted and related to structure/function relationships and pathogenetic responses to some selected inhaled toxicants. In the aggregate, there is remarkable homogeneity in form and function among the species. Morphologic aspects of the respiratory tract and lung defense mechanisms are qualitatively similar among species. On the other hand, quantitative differences between humans and experimental animals are known to exist with respect to deposition and mucociliary clearance of inhaled particulates, and these factors are likely to influence the dose that is delivered to specific target sites in the lung. It is interesting to consider that pathologic cellular events following asbestos, ozone, and nitrogen dioxide exposure are likely to occur at similar sites in humans, nonhuman primates, and rodents. In this respect, it has been demonstrated that the early lesions of asbestos-induced lung disease in both rats and humans are initiated at similar anatomical sites, i.e., the junctions of terminal airways and alveolar regions. PMs and complement-mediated mechanisms have been implicated in the development of asbestosis in rats; however, it remains to be determined whether complement activation plays an important role in human asbestosis, although pulmonary and interstitial macrophages clearly are associated with the fibrogenic process associated with this restrictive lung disease. The toxic pulmonary effects following ozone exposure have been well studied in rodents and nonhuman primates. It has been established that distal airway and alveolar epithelial cells are principal targets of oxidant pollutants, and this is well supported by dosimetry considerations, morphologic observations, and morphometric analyses. Chronic ozone exposure in rats and monkeys causes epithelial injury at the level of the terminal bronchiole and proximal alveolar regions of the lung.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats

Ferric oxide (Fe(2)O(3)) nanoparticles are of considerable interest for application in nanotechnology related fields. However, as iron being a highly redox-active transition metal, the safety of iron nanomaterials need to be further studied. In this study, the size, dose and time dependent of Fe(2)O(3) nanoparticle on pulmonary and coagulation system have been studied after intratracheal instillation. The Fe(2)O(3) nanoparticles with mean diameters of 22 and 280 nm, respectively, were intratracheally instilled to male Sprague Dawley rats at low (0.8 mg/kgbw) and high (20 mg/kgbw) doses. The toxic effects were monitored in the post-instilled 1, 7 and 30 days. Our results showed that the Fe(2)O(3) nanoparticle exposure could induce oxidative stress in lung. Alveolar macrophage (AM) over-loading of phagocytosed nanoparticle by high dose treatment had occurred, while the non-phagocytosed particles were found entering into alveolar epithelial in day 1 after exposure. Several inflammatory reactions including inflammatory and immune cells increase, clinical pathological changes: follicular hyperplasia, protein effusion, pulmonary capillary vessel hyperaemia and alveolar lipoproteinosis in lung were observed. The sustain burden of particles in AM and epithelium cells has caused lung emphysema and pro-sign of lung fibrosis. At the post-instilled day 30, the typical coagulation parameters, prothrombin time (PT) and activated partial thromboplastin time (APTT) in blood of low dose 22 nm-Fe(2)O(3) treated rats were significantly longer than the controls. We concluded that both of the two-sized Fe(2)O(3) particle intratracheal exposure could induce lung injury. Comparing with the submicron-sized Fe(2)O(3) particle, the nano-sized Fe(2)O(3) particle may increase microvascular permeability and cell lysis in lung epitheliums and disturb blood coagulation parameters significantly.