Nonprotein sulfhydryl alterations in F-344 rats following acute methyl chloride inhalation

This study examined the effect of acute methyl chloride (MeCl) inhalation on F-344 rat tissue nonprotein sulfhydryl (NPSH), largely reduced glutathione. Rats were exposed to MeCl concentrations of 1500, 500, or 100 ppm. A 6-hr exposure to 1500 ppm of MeCl decreased the NPSH content of liver, kidney, and lungs to 17, 27, and 30% of control values, respectively, while 500 ppm MeCl lowered the liver, kidney, and lung NPSH to 41, 59, and 55% of control values, respectively, demonstrating a concentration-related effect. Blood NPSH did not differ from controls in either of these groups. No statistically significant changes from controls in tissue or blood NPSH were observed following a 100-ppm MeCl exposure. The extent of tissue NPSH loss was dependent on exposure duration. Liver and kidney NPSH returned to control NPSH concentrations within 8 hr following exposure of 1500 ppm MeCl. Pretreatment of rats with Aroclor-1254 or SKF-525A did not alter the MeCl-induced decrease in tissue NPSH. These data indicate that MeCl reacts extensively with tissue NPSH in vivo in a concentration-related fashion following acute inhalation exposure. The most likely NPSH constituent with which MeCl reacts is reduced glutathione. The finding that blood NPSH was not affected, in contrast to liver, kidney, or lung NPSH, indicates a tissue-specific reaction between MeCl and sulfhydryl groups, a reaction in which the tissue enzyme glutathione-S-alkyltransferase may play a role.     

Effects of short-term inhalation of cadmium oxides on rabbit pulmonary microsomal enzymes

Rabbits, guinea pigs, rats and mice were compared for the activity of benzo[a]pyrene hydroxylase. aminopyrine N-demethylase and aniline hydroxylase of pulmonary microsomes. The activity of the microsomal enzymes was highest in rabbits, followed by guinea pigs and then rats and mice. Effects of the inhalation of cadmium oxides (CdO) were studied on the pulmonary microsomal enzymes in male rabbits. Rabbits were exposed for 15 min to air containing microparticles of CdO at four different concentrations ranging from 6.4 ± 0.5 to 22.4 ± 0.4 mg Cd/m³. The animals were killed 24 hr after the inhalation of CdO. The lung weight of the animals was increased markedly at doses higher than 12.6 mg/m³, the increase attaining 50 per cent increase at the highest dose. The activity of benzo[a]pyrene hydroxylase was reduced significantly at the higher doses, the reduction being dose-dependent reaching 50 per cent reduction. The activity of aminopyrine N-demethylase and aniline hydroxylase was reduced moderately by CdO inhalation but the reduction was not dose-dependent. Time-course effects of CdO inhalation on the pulmonary microsomal enzymes were studied on the rabbits exposed for 15 min to air containing CdO at concentrations of 13.0 ± 0.3 mg Cd/m³. The animals were killed 0.5, 1, 2, 4, and 6 days after the inhalation. The body weight increase was less in the treated groups than in the controls and edematous lesions in the lung were observed in most of the treated animals. The lung weight was increased after the inhalation, reaching its plateau on day 4. The activity of the microsomal enzymes was reduced throughout the experimental period, the maximum reduction being obtained on day 2 after the inhalation except for aniline hydroxylase that was reduced at the same degree throughout the experimental period.     

Pulmonary alterations associated with inhalation of occupational and environmental irritants.

Many gases, vapors, or particles found in occupational and/or environmental settings can act as irritants. In the present study, sensory irritants are characterized by the stimulation of neuropeptide release from sensory nerves in the nasal mucosa, while pulmonary irritants are characterized by recruitment of PMN into bronchoalveolar airspaces, elevation of breathing frequency, and neuropeptide release from sensory fibers innervating the epithelium of the conducting airways. A review of data from our laboratory as well as results from others indicate that asphalt fume is a sensory irritant; toluene diisocyanate (TDI), methyl isocyanate, and machining fluid act as both sensory and pulmonary irritants; while cotton dust, agricultural dusts, microbial products, leather conditioner, and ozone exhibit responses characteristic of pulmonary irritants.     

Biopersistence of rock wool in lungs after short-term inhalation in rats

To evaluate the safety of rock wool (RW), an asbestos substitute, we examined the biopersistence of RW fibers in rat lungs based on the changes of fiber number and fiber size (length and diameter) by a nose-only inhalation exposure study. Twenty-four male Fischer 344 rats were exposed to RW fibers at a concentration of 30 mg/m(3) continuously for 3 h daily for 5 consecutive days. Six rats each were sacrificed shortly and at 1, 2, and 4 wk after exposure, and their lung tissues were ashed by a low-temperature plasma asher. Then the fiber numbers and fiber sizes in lungs were determined using a phase-contrast microscope and computed image analyzer. During the study period, the arithmetic mean (SD) values of fiber and weight concentrations were 78.5 (35.7) fibers/cm(3), and 29.9 (28.3) mg/m(3), respectively. The fiber number in lungs 4 wk after exposure significantly decreased from the baseline value (shortly after exposure) (p < .05). The half-life of fibers calculated from the approximate curve was 28 days for all fibers and 16 days for fibers with L > 20 microm, and the rate of decrease in fiber number was 46.3% at 4 wk after exposure (shortly-after group = 100%). Likewise, both length and diameter significantly decreased at 4 wk after exposure (p < .05), probably because fibers were phagosytosed and digested by alveolar macrophages, discharged to outside of the body by mucociliary movement, or dissolved by body fluid. It will be necessary in the future to further confirm the safety of RW fibers by assessing the biopersistence of fibers in the lungs and their pathological effects in our ongoing study performed in accordance with the guidelines established in the "Methods for Determination of Hazardous Properties for Human Health of Man Made Mineral Fibers" (EC protocol).     

Differential alterations in levels of hepatic microsomal cytochrome P450 isozymes following intracerebroventricular injection of bacterial lipopolysaccharide in rats

To investigate the effect of central inflammation due to bacterial infection, such as meningitis, on the activities of hepatic cytochromes P450 (CYPs), rats were injected intracerebroventricularly (i.c.v.) with 0.1 μ g of bacterial lipopolysaccharide (LPS). The LPS i.c.v. injection significantly decreased the total P450 contents (by 30% of the levels of control rats treated with saline i.c.v.), the contents of CYP1A (48%), 2B (54%), 2C11 (37%) and 3A (40%) and related drug metabolizing activities, 7-ethoxycoumarin O-deethylation (36%), imipramine N-demethylation (41%) and erythromycin N-demethylation (33%) in liver microsomes 24 h after the treatment. In contrast, intraperitoneal (i.p.) injection of LPS at the same dose as i.c.v. (0.1 μ g) did not significantly affect the hepatic microsomal contents of total P450 or the content of each individual CYP isozyme and its activity. CYP2D1 protein and the activity of imipramine 2-hydroxylase were not significantly decreased by LPS injection regardless of the route of administration. The inhibitory effects of 0.1 μg i.c.v. LPS on the activities of these CYPs were almost equal to those of 10 μg i.p. LPS, and 0.01 μg of i.c.v. LPS significantly decreased the activity of imipramine N-demethylase only. Therefore, the LPS i.c.v. injection resulted in CYP isozyme-selective inhibition at an ineffective dose when injected i.p.. It is suggested that a central inflammation, such as meningitis, differentially decreases the levels of hepatic CYP isozymes. A possible involvement is discussed of the central nervous system in this down-regulation. Received: 2 September 1997 / Accepted: 5 May 1998     

Lung sulfhydryl changes in rats following chlorine inhalation

Respiratory tract irritation by chlorine (Cl₂) may be associated with tissue sulfhydryl (-SH) oxidation. This study examined the effects of Cl₂ on lung -SH content and on the enzymes which maintain non-protein -SH levels, glucose-6-phosphate dehydrogenase (G-6PD) and glutathione reductase (GSSG-RED). Male Fischer-344 rats were exposed to 12 ppm Cl₂, 6 hr/day for 1,5, or 10 days. Following Cl₂ exposure, rats were sacrificed immediately or after a 3- to 17-day recovery period. A study using pair-fed nonexposed rats was carried out to clarify possible nonspecific malnutrition effects. No alterations in lung protein -SH, nonprotein -SH, G-6PD, or GSSG-RED were observed in rats sacrificed immediately following 1, 5, or 10 days of Cl₂ exposure. Rats allowed to recover 3 days following 10 days of Cl₂ treatment had a 20% increase in lung -SH above the values for controls fed ad libitum while G-6PD and GSSG-RED activities increased 98 and 39% above controls, respectively. Similar increases in lung -SH, G-6PD, and GSSG-RED were observed after 6 days recovery. Biochemical alterations returned to control values by 10 days recovery. The observed increases in pulmonary -SH, G-6PD, and GSSG-RED were not the result of decreased food consumption. In conclusion, oxidation of lung -SH content immediately following Cl₂ exposure was not observed. An increase in lung -SH and enzyme activities during recovery periods may reflect reparative processes subsequent to Cl₂-induced lung damage.     

Assessment of the hepatotoxicity of acute and short-term exposure to inhaled p-xylene in F-344 rats

Due to the ubiquitous presence of p-xylene in air and the existing uncertainty regarding its hepatotoxic potential, we examined the effect of acute and short-term exposure to inhaled p-xylene on the liver. Male F-344 rats were exposed to 0 or to 1600 ppm p-xylene, 6 h/d, for 1 or 3 d. Exposure to inhaled p-xylene caused no histopathological evidence of hepatic damage and had little or no effect on the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ornithine carbamyl transferase, alkaline phosphatase, and total bilirubin. Exposure to p-xylene for 1 or 3 d resulted in an increase in relative liver weight on d 1 post-exposure. The concentration of hepatic cytochrome P-450 was increased by both p-xylene exposure regimens on d 1 postexposure and had returned to control levels by d 3 following the single p-xylene exposure and by d 2 following the 3-d exposure. These observations provide consistent evidence that acute and short-term exposure to 1600 ppm p-xylene by inhalation did not produce overt hepatotoxicity but resulted in a significant increase in the concentration of hepatic cytochrome P-450, the principal enzyme system involved in the metabolic biotransformation of xenobiotics.     

Long- and short-term changes in the neuroimmune-endocrine parameters following inhalation exposures of F344 rats to low-dose sarin.

Inhalation of subclinical doses of sarin suppresses the antibody-forming cell (AFC) response, T-cell mitogenesis, and serum corticosterone (CORT) levels, and high doses of sarin cause lung inflammation. However, the duration of these changes is not known. In these studies, rats were exposed to a subclinical dose of sarin (0.4 mg/m3/h/day) for 1 or 5 days, and immune and inflammatory parameters were assayed up to 8 weeks before sarin exposure. Our results showed that the effects of a 5-day sarin exposure on the AFC response and T-cell receptor (TCR)-mediated Ca2+ response disappeared within 2-4 weeks after sarin exposure, whereas the CORT and adrenocorticotropin hormone (ACTH) levels remained significantly decreased. Pretreatment of rats with chlorisondamine attenuated the effects of sarin on the AFC and the TCR-mediated Ca2+ response, implicating the autonomic nervous system (ANS) in the sarin-induced changes in T-cell function. Moreover, exposure to a single or five repeated subclinical doses of sarin upregulated the mRNA expression of proinflammatory cytokines in the lung, which is associated with the activation of NFkappaB in bronchoalveolar lavage cells. These effects were lost within 2 weeks of sarin inhalation. Our results suggest that while sarin-induced changes in T cells and cytokine gene expression were short lived, suppression of CORT and ACTH levels were relatively long lived and might represent biomarkers of sarin exposure. Moreover, while the effects of sarin on T-cell function were regulated by the ANS, the decreased CORT levels by sarin might result from its effects on the hypothalamus-pituitary-adrenal axis.     

Pulmonary effects of ultrafine and fine ammonium salts aerosols in healthy and monocrotaline-treated rats following short-term exposure

In the present study the effects of a 3-day inhalation exposure to model compounds for ambient particulate matter were investigated: ammonium bisulfate, ammonium ferrosulfate, and ammonium nitrate, all components of the secondary aerosol fraction of ambient particulate matter (PM), and carbon black (CB, model aerosol for primary PM). The objective of this study was to test the hypothesis that secondary model aerosols exert acute pulmonary adverse effects in rats, and that rats with pulmonary hypertension (PH), induced by monocrotaline (MCT), are more sensitive to these components than normal healthy animals. An additional aim was to test the hypothesis that fine particles exert more effects than ultrafines. Healthy and PH rats were exposed to ultrafine (mass median diameter [MMD] approximate, equals 0.07-0.10 microm; 4 x 10(5) particles/cm(3)) and fine (MMD approximate, equals 0.57-0.64 micro;m; 9 x 10(3) particles/cm(3)) ammonium aerosols during 4 h/day for 3 consecutive days. The mean mass concentrations ranged from 70 to 420 microg/m(3), respectively, for ultrafine ammonium bisulfate, nitrate, and ferrosulfate and from 275 to 410 microg/m(3) for fine-mode aerosols. In an additional experiment, simultaneous exposure to a fine CB aerosol (0.6 microm; 2-9 mg/m(3)) and ammonium nitrate (0.4-18 mg/m(3)) was performed. Bronchoalveolar lavage fluid (BALF) analysis and histopathological examination were performed on animals sacrificed 1 day after the last exposure. Histopathology of the lungs did not reveal test atmosphere-related abnormalities in either healthy or PH rats exposed to the ammonium salts, or to a combination of CB + nitrate. Alveolar macrophages in rats exposed to CB only revealed the presence of black material in their cytoplasm. There were no signs of cytotoxicity due to the aerosol exposures (as measured with lactate dehydrogenase [LDH], protein, and albumin contents in BALF). Macrophages were not activated after MCT treatment or the test atmospheres, since no changes were observed in N-acetyl glucosaminidase (NAG). Cell differentiation profiles were inconsistent, partly caused by an already present infection with Haemophilus sp. However, we believe that the test atmospheres did not affect cell differentiation or total cell counts. The results show that at exposure levels of ammonium salts at least one order of magnitude higher than ambient levels, marked adverse health effects were absent in both healthy and PH rats.     

Pulmonary toxicity of printer toner following inhalation and intratracheal instillation

Abstract

The pulmonary effects of a finished toner were evaluated in intratracheal instillation and inhalation studies, using toners with external additives (titanium dioxide nanoparticles and amorphous silica nanoparticles). Rats received an intratracheal dose of 1?mg or 2?mg of toner and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months. The toner induced pulmonary inflammation, as evidenced by a transient neutrophil response in the low-dose groups and persistent neutrophil infiltration in the high-dose groups. There were increased concentrations of heme oxygenase-1 (HO-1) as a marker of oxidative stress in the bronchoalveolar lavage fluid (BALF) and the lung. In a 90-day inhalation study, rats were exposed to well-dispersed toner (mean of MMAD: 3.76?µm). The three mass concentrations of toner were 1, 4 and 16?mg/m³ for 13 weeks, and the rats were sacrificed at 6 days and 91 days after the end of the exposure period. The low and medium concentrations did not induce neutrophil infiltration in the lung of statistical significance, but the high concentration did, and, in addition, upon histopathological examination not only showed findings of inflammation but also of fibrosis in the lung. Taken together, the results of our studies suggest that toners with external additives lead to pulmonary inflammation and fibrosis at lung burdens suggest beyond the overload. The changes observed in the pulmonary responses in this inhalation study indicate that the high concentration (16?mg/m³) is an LOAEL and that the medium concentration (4?mg/m³) is an NOAEL.     

Behavioral effects of acute p-xylene inhalation in rats: autoshaping, motor activity, and reversal learning

p-Xylene is a ubiquitous solvent and chemical precursor used in industry, gasoline, and household products. While the population at risk for exposure is thus quite large, little is known about its neurobehavioral effects. To evaluate the possibility that p-xylene affects cognitive behavior, male Long-Evans hooded rats inhaled p-xylene at concentrations of 0 or 1600 ppm, 4 hr per day for 1 to 5 days, and were evaluated after exposure on two learning tasks and a test of motor activity. Autoshaping was carried out across 5 successive days with p-xylene exposure in the morning followed by testing in the afternoon. For this test, the retraction of a single response lever on a variable-time 35-sec schedule was followed by delivery of a food pellet. When the force required to depress the lever was low (0.10 N), response acquisition was faster in animals having inhaled 1600 ppm p-xylene than in air-exposed controls. When the force was increased to 0.20 N, however, p-xylene-exposed rats acquired the response no faster than controls. In contrast, inhaled p-xylene at 1600 ppm suppressed response rates in an automaintained reversal learning paradigm without affecting reversal rate. Studies of motor activity showed that while vertically-directed activity was unaffected by p-xylene, horizontally-directed activity was increased by about 30% for the first 15 min of each daily 25-min test. This p-xylene-induced hyperactivity returned to control levels within each daily test and declined across the 5 daily tests, but was still evident on the fifth day. Rats tested 3.5 hr after termination of p-xylene inhalation were not less hyperactive than rats tested 0.5 hr after exposure. Increased horizontally-directed activity was not correlated across animals with the enhancement of autoshaping. These results were interpreted to indicate that p-xylene inhalation at 16 times the TLV induced hyperactivity and facilitated autoshaping by different means, and that the facilitation of autoshaping involved a change in response topography and not a direct effect on learning ability per se.     

Pulmonary and systemic effects of short-term inhalation exposure to ultrafine carbon black particles

While environmental particles are associated with mortality and morbidity related to pulmonary and cardiovascular (CV) disease, the mechanisms involved in CV health effects are not known. Changes in systemic clotting factors have been associated with pulmonary inflammation. We hypothesized that inhaled ultrafine particles result in an inflammatory response which may stimulate systemic clotting factor release. Adult male Wistar rats were exposed to either fine or ultrafine carbon black (CB) for 7 h. The attained total suspended particle concentrations were 1.66 mg/m³ for ultrafine CB and 1.40 mg/m³ for fine CB. Particle concentration of ultrafine particles was more than 10 times greater than that of fine particles and the count median aerodynamic diameter averaged 114 nm for the ultrafine and 268 nm for the fine carbon particles. Data were collected immediately, 16 and 48 h following exposure. Only ultrafine CB caused an increase in total bronchoalveolar lavage (BAL) leukocytes, whereas both fine (2-fold) and ultrafine (4-fold) carbon particles caused an increase in BAL neutrophils at 16 h postexposure. Exposure to the ultrafine, but not fine, carbon was also associated with significant increases in the total numbers of blood leukocytes. Plasma fibrinogen, factor VII and von Willebrand factor (vWF) were unaffected by particle treatments as was plasma Trolox equivalent antioxidant status (TEAC). Macrophage inflammatory protein-2 mRNA was significantly increased in BAL cells 48 h following exposure to ultrafine CB. The data show that there is a small but consistent significant proinflammatory effect of this exposure to ultrafine particles that is greater than the effect of the same exposure to fine CB.     

Region-dependent alterations in glutamate and GABA measured by high-resolution magnetic resonance spectroscopy following acute binge inhalation of toluene in juvenile rats

Little is known about the neurochemical effects accompanying the high-concentration inhalant exposures characteristic of binge solvent abuse. In adult animals, prior studies with other patterns of exposure indicate that toluene, a commonly abused household and industrial solvent, has significant effects on the glutamatergic and GABAergic neurotransmitter systems and on other neurotransmitter systems as well. In the current investigation, high-resolution "magic angle" spinning proton magnetic resonance spectroscopy (HR-MAS (1)H-MRS) was used to assess the effect of acute binge toluene inhalation on regional brain concentrations of various neurochemicals including glutamate (GLU), GABA, and glutamine (GLN) in juvenile male and female rats. Acute toluene (8000 ppm or 12,000 ppm) significantly reduced levels of hippocampal GABA (-12%) and GLU (-8%), and the GLU/GLN ratio, an index of glutamatergic tone, was significantly reduced (-22%) in the dorsal anterior striatum, driven largely by a 28% increase in GLN. Significant increases in alanine and lactate in several brain regions after acute toluene may be indicative of altered oxygen-dependent metabolism associated with the inhalation of higher concentrations of toluene (e.g., >5000 ppm). Other components of the MR-visible neurochemical profile, such as N-acetylaspartate (NAA), myo-inositol, creatine, and various choline containing compounds, were unchanged by acute toluene. The results are consistent with the notion that binge toluene exposure affects juvenile neurochemistry in systems mediating the rewarding and emotional aspects of substance abuse. Moreover the results provide a framework to understand further (1)H-MRS studies in clinical populations.     

Pulmonary responses and recovery following single and repeated inhalation exposure of rats to polymeric methylene diphenyl diisocyanate aerosols

Acute and repeated inhalation exposures (for 28 days) to polymeric methylene diphenyl diisocyanate (PMDI) were performed in rats. Investigations were made at the end of exposures and after 3, 10 and 30 days of recovery following single acute exposures and after 30 days of recovery following 28 days of exposure. Acute exposures to 10, 30 or 100 mg m(-3) PMDI produced clinical signs in all animals that were consistent with exposure to irritant aerosols. An exposure concentration-related body weight loss and increase in lung weight were seen post-exposure, with complete recovery by day 8. The time course of changes in the lung over the initial days following exposure consisted of a pattern of initial toxicity, rapid and heavy influx of inflammatory cells and soluble markers of inflammation and cell damage, increased lung surfactant, a subsequent recovery and epithelial proliferative phase and, finally, a return to the normal status quo of the lung. During these stages there was evidence for perturbation of lung surfactant homeostasis, demonstrated by increased amounts of crystalline surfactant and increased number and size of lamellar bodies within type II alveolar cells.Repeated exposure over 28 days to the less toxic concentrations of 1, 4 or 10 mg m(-3) PMDI produced no clinical signs or body weight changes, but an increase in lung weight was seen in animals exposed to 10 mg m(-3), which resolved following the 30-day recovery period. Other effects seen were again consistent with exposure to irritant aerosols, but were less severe than those seen in the acute study. Analysis of bronchoalveolar lavage fluid revealed similar changes to those seen in the acute study. At both 10 and 4 mg m(-3) PMDI increased numbers of 'foamy' macrophages in lung lavage cell pellet correlated with the increased phospholipid content of the pellet. Changes in lung lavage parameters and electron microscopic evidence again suggested perturbations in surfactant homeostasis. Histologically, bronchiolitis and thickening of the central acinar regions was seen at 10 and 4 mg m(-3), reflecting changes in cell proliferation in the terminal bronchioles and centro-acinar regions. Almost all effects seen had recovered by day 30 post-exposure.Both acute and subacute studies demonstrate rapid recovery of effects in the lung following exposure to PMDI, with no progression of these effects even at concentrations higher than those shown to produce tumours in a chronic study. These findings add weight to the hypothesis that pulmonary tumours seen following chronic exposure to PMDI are most likely due to a combination of the chronic irritant effects of repeated exposure, coupled with the presence of insoluble polyureas formed by polymerization of PMDI (found in studies reported here and previous chronic studies), and therefore acute or short-term exposures to PMDI are likely to be of little concern for long-term pulmonary health.     

短时间吸入七氟醚对幼鼠海马神经元的影响

目的研究短时间吸入七氟醚对发育中大鼠海马神经元凋亡的影响。方法 78只1个月龄SD大鼠按随机数字表法随机分为3组,空气对照组(Sa,26只),载气对照组(Sc,26只),3%七氟醚吸入2 h组(S2,26只),建立七氟醚吸入模型,吸入结束后12 h用旷场实验和T迷宫进行神经行为学测试,同时断头取海马组织,苏木素-伊红染色观察海马神经元形态学改变,用流式细胞仪检测凋亡,激光共聚焦显微镜测神经元细胞内游离钙离子浓度。结果 S2组海马凋亡神经元数目以及神经元内游离钙离子相对荧光像素值均高于对照组,差异有统计学意义(P<0.05);但神经行为学检测无明显差别。结论七氟醚可诱导幼龄大鼠海马神经元凋亡,可能通过升高细胞内钙离子浓度而触发凋亡。但单次、短时间吸入(<2 h)七氟醚引起的神经元凋亡无明显神经行为学意义。     

Cytogenetic analysis of lymphocytes from rats following formaldehyde inhalation

Male and female Fischer-344 rats were exposed to target concentrations of 0.5, 6, or 15 ppm formaldehyde by inhalation for 6 h/day for 5 days. Blood was removed by cardiac puncture within 1 h following termination of exposures and cultured in the presence of 5-bromodeoxyuridine (BrdU) (4 μM) for analyses of sister-chromatid exchange (SCE) and chromosome breakage. Formaldehyde did not cause a statistically significant increase in either SCE frequency or in the number of metaphases displaying chromosome aberrations.     

Respiratory tract responses in male rats following subchronic acrolein inhalation

The goal of this study was to characterize the respiratory tract toxicity of acrolein, including nasal and pulmonary effects, in adult male F344 rats. Animals underwent whole-body exposure to 0, 0.02, 0.06, 0.2, 0.6, or 1.8 ppm acrolein for 6 hr/day, five days/week for up to 65 exposure days (13 exposure weeks). Respiratory tract histopathology was evaluated after 4, 14, 30, and 65 exposure days, as well as 60 days after the end of the 13 week exposure. Acrolein exposure was associated with reduced body weight gain. Rats exposed to > or = 0.06 ppm acrolein had depressed terminal body weights when compared with air-exposed controls. Histologic evaluation of the nasal cavity showed olfactory epithelial inflammation and olfactory neuronal loss (ONL) following exposure to 1.8 ppm acrolein. Moderately severe ONL in the dorsal meatus and ethmoid turbinates occurred within four days while septal involvement developed with ongoing exposure. A rostral-caudal gradient in lesion severity was noted, with the anterior portion of the nasal cavity being more severely affected. Acrolein exposure was associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. The lateral wall was amongst the most sensitive locations for these responses and increased respiratory epithelial cell proliferation occurred at this site following 4 to 30 days of exposure to > or = 0.6 ppm acrolein. The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein.     

Bronchoalveolar lavage in rats and mice following beryllium sulfate inhalation

The effects of lung injury in rats and mice exposed to an aerosol of beryllium sulfate for 1 hr through nose-only inhalation were evaluated by the method of bronchoalveolar lavage. The lavage fluid of rats exposed to an aerosol of either 3.3 or 7.0 micrograms Be/liter over a 21-day period following exposure indicated lactate dehydrogenase (LDH) and alkaline phosphatase (Alk Pase) activities to be the most sensitive indicators of lung damage. LDH activity peaked at 8 days postexposure while Alk Pase activity was maximum at Day 5. Both values were 30 times greater than comparable controls at these time points. Acid phosphatase activity and albumin levels also increased over the 21-day period, but not to the same extent. The lung lavage of mice exposed to 7.2 micrograms Be/liter showed LDH activity as the most sensitive indicator of lung damage with a maximum response three times greater than that of controls at Day 5.     

Pulmonary changes in the rat following low phosgene exposure

Minimal inhalation doses (or concentrations) of phosgene necessary for the production of changes within the blood-air barrier were determined in rats. At least 50 ppm.min (5 ppm×10 min) was necessary for the production of alveolar oedema (the minimal effective phosgene concentration being 5 ppm). While the smallest phosgene dose to produce an increase in pulmonary lavage protein content was also 50 ppm.min and while the smallest phosgene dose to produce widening of pulmonary interstices was 25 ppm.min, there was no phosgene threshold concentration (down to 0.1 ppm) for these two latter parameters, which are assumed to be indicators of physiological compensatory mechanisms within the blood-air barrier.The primary localisation of pulmonary damage seemed to depend on the concentration of phosgene used: at low concentrations (0.1–2.5 ppm) the changes were primarily located at the transition from terminal brochioles to the alveolar ducts; at higher concentrations (5 ppm) damage to the alveolar pneumocytes (type I) was more conspicuous.Dedicated to Professor Dr. Dr. H. Meessen