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.     

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m³ concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m³ soman survived, while animals exposed to 841, and 1121 mg/m³ resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt₅₀ for soman determined by probit analysis was 827.2 mg/m³. A majority of the animals that died at 1121 mg/m³ developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.     

Genetic differences in the induction of aryl hydrocarbon hydroxylase and its components by 3-methylcholanthrene in liver and lung microsomes among four strains of guinea pigs

Four strains of guinea pigs (Hartley, No. 2, No. 13 and JY-1) were examined for the effects of intraperitoneal treatment with 3-methylcholanthrene on aryl hydrocarbon hydroxylase activity, total cytochrome P-450 content in liver and lung microsomes, and NADPH-cytochrome c reductase activity in liver microsomes. Following treatment with 3-methylcholanthrene at a dose of 50 mg/kg body weight, aryl hydrocarbon hydroxylase activity and cytochrome P-450 content in liver were both increased in all the strains used, and the activity of NADPH-cytochrome c reductase in liver was also increased in all strains except No. 13. While the cytochrome P-450 content in lung was increased in all the strains except No. 13, there was no increase in the aryl hydrocarbon hydroxylase activity in lung from any strain of guinea pig examined. When the dose of 3-methylcholanthrene was increased to 250 mg/kg body weight, an apparent induction of aryl hydrocarbon hydroxylase was detected in the lung from the Hartley strain of guinea pigs, but not in the other three strains. In summary, marked differences were seen in sensitivity to 3-methylcholanthrene between liver and lung, and apparent strain differences were observed among the guinea pigs used in this experiment.     

Combined treatment with 2'-nor-cGMP and ganciclovir against cytomegalovirus infection in a guinea pig model.

The combination 2'-nor-cGMP/DHPG at fixed ratios 1:5, 1:10 and 1:20 showed synergistic antiviral effects against GPCMV replication in vitro with CI value < 1. In vivo, a fixed ratio of 1:10 at three different dosage levels of 1.25/12.5 mg, 2.5/25 mg and 5/50 mg/kg/day 2'-nor-cGMP/DHPG combination showed only additive results when compared with each drug alone. However, synergistic antiviral effects were obtained when infected guinea pigs were treated with 2'-nor-cGMP/DHPG combination 2.5/10 mg/kg/day (1:4). A significantly lower GPCMV infectivity titer was noted in the salivary gland, lung and spleen of infected guinea pigs treated with the combination of 2'-nor-cGMP/DHPG 2.5/10 mg/kg/day, as compared to animals treated with a corresponding dose of each drug alone. In addition, GPCMV-infected animals treated with the latter combination showed increased body weight than when either drug was used alone. Histopathologically, each drug alone reduced the viral induced changes in the lung and spleen, but the combination therapy reduced these changes still further. Toxic changes seen in the kidney and bone marrow of infected animals treated with 2'-nor-cGMP, 2.5 mg/kg/day were not significantly increased when DHPG 10 mg/kg/day was added to the regimen. Therefore, combined treatment with 2'-nor-cGMP/DHPG in appropriate concentration is more helpful for acute cytomegalovirus infection in guinea pigs than when either drug was used alone.     

The inhalation toxicity of sulfolane (tetrahydrothiophene-1,1-dioxide)

The mean survival time (MST) of rats exposed to 11,000 mg of aerosolized sulfolane/m³ was 19.4 hr and all rats convulsed during the exposure. The sulfolane concentration expected to yield a MST of 24 hr was calculated to be 4700 mg/m³. After less than 24 hr of exposure, leukopenia and convulsions were observed in rats (3600 mg/m³) or squirrel monkeys (4850 mg/m³) exposed to high concentrations of aerosolized sulfolane. Six subacute exposures were conducted: one repeated exposure to 495 mg/m³ for 8 hr/day, 5 days/week for 27 exposure days and five 23 hr/day, continuous exposures of approximately 90-day duration to 200, 159, 20, 4.0, and 2.8 mg/m³. Squirrel monkeys convulsed, vomited, and died during the exposures to 495 and 200 mg/m³. Dogs convulsed, vomited, and were unusually aggressive during continuous exposure to 200 mg/m³, but not during repeated exposures to 495 mg/m³. Rodents did not convulse in any of these subacute exposures. Leukopenia and increased plasma transaminase activity were found in guinea pigs exposed to 200 mg/m³, but not those exposed to 159 mg/m³. Hemorrhagic, inflamed lungs were also observed in most animals exposed to the two highest concentrations. In this study, no overt toxic effects were noted during exposure of rats, guinea pigs, squirrel monkeys, or dogs to 20, 4.0, or 2.8 mg of sulfolane/m³.     

Assessment of early acute lung injury in rodents exposed to phosgene

Phosgene is a highly reactive oxidant gas used in the chemical industry. Phosgene can cause life-threatening pulmonary edema by reacting with peripheral lung compartment tissue components. Clinical evidence of edema is not usually apparent until well after the initial exposure. This study was designed to investigate early signs of acute lung injury in rodents within 45–60 min after the start of exposure. Male mice, rats, or guinea pigs were exposed to 87 mg/m³ (22 ppm) phosgene or filtered room air for 20 min followed by room air washout for 5 min. This concentration-time exposure causes a doubling of lung wet weight within 5 h. After exposure, animals were immediately anesthetized i.p., with pentobarbital. Bronchoalveolar lavage (BAL) was performed and fluid analyzed for total glutathione (GSH), lipid peroxidation thiobarbituric acid reactive substances (TBARS), and protein concentration. Lungs were perfused with saline to remove blood, freeze-snapped in liquid N₂, analyzed for tissue GSH, and TBARS. Lung edema was assessed gravimetrically by measuring tissue wet/dry (W/D) weight ratios and tissue wet weights (TWW). W/D and TWW were significantly higher in mice for phosgene vs air (P=0.001, P<0.0001, respectively), but not in rats or guinea pigs. Tissue TBARS was significantly higher in phosgene-exposed guinea pigs, P=0.027; however, BAL TBARS was higher in both rats and guinea pigs, P=0.013 and P=0.006, respectively. Tissue GSH was significantly lower in phosgene-exposed rats and guinea pigs but not mice, whereas BAL GSH was higher in rats, P<0.0001. There were significantly higher BAL protein levels in all phosgene-exposed species: mice, P<0.0001; rats, P<0.0001; and guinea pigs, P=0.002. Although there appears to be a species-specific biochemical effect of phosgene exposure for some biochemical indices, measurement of BAL protein in all three species is a better indicator of ensuing edema formation. Received: 30 June 1997 / Accepted: 5 January 1998     

Chronic Inhalation Exposure of Wistar Rats and two Different Strains of Mice to Diesel Engine Exhaust,Carbon Black,and Titanium Dioxide

Abstract

Wistar rats were exposed for 2 yr to diesel engine exhaust, carbon black (Printex 90, Degussa, FR. G), and ultraline TiO₂ (P25, Degussa, FRG) and were subsequently kept in clean air for 6 mo. Particle exposure concentration was increased during the course of the experiment for carbon black and TiO₂ to reach particle lung loads similar to those found in the diesel soot-exposed rats. The average particle exposure concentrations for diesel soot, carbon black, and TiO₂ were 7, 11.6, and 10 mg/m³, respectively. Lung tumor rates in these rats increased with increasing cumulative particle exposure (mg/m³ x h) independent of the type of particle employed. The exposure to 2.5 mg/m¹ diesel soot also induced a significantly increased lung tumor rate, but 0.8 mg/m³ diesel soot did not. With this study, it could be demonstrated that the carbon core of diesel soot is mainly responsible for the occurrence of diesel engine exhaust-related lung tumors; the role of diesel soot-attached polycyclic aromatic hydrocarbons (PAH) and NO₂-PAH is probably of minor importance in the rat lung. Agglomerates of ultrafine carbon and TiO₂ particles seem particularly suited to exert toxic effects primarily on alveolar macrophages and alveolar lung particle clearance. Although such lung toxic effects were also seen with the lowest diesel soot exposure concentration (0.8 mg/m³) used, no increased lung tumor rate was detected in this group of rats. Whether this result implies a threshold for the particle-related lung tumor induction mechanism as already discussed by Vostal (1986) or whether the tumor effect was simply not observed because of statistical reasons needs further research on the possible mode of action of ultra-fine insoluble particles in the lung. NMR. I mice that were kept in the same exposure atmospheres (high diesel soot, carbon black, TiO₂) as the rats did not show an increased lung tumor rate. Furthermore, there was no treatment-related tumor response in NMRI nor in C57BL/6N mice exposed to diesel exhaust containing 4.5 mg/m³ diesel soot or to the same exhaust dilution but devoid of soot particles. C57BU6N mice were exposed for 24 mo and were subsequently kept in clean air for another 6 mo. Not only the average survival time but also the particle load per gram lung wet weight of the C57BU6N mice was very similar to rats exposed to 7 mg/m³ diesel soot.     

Endotracheal aerosolization of atropine sulfate protects against soman-induced acute respiratory toxicity in guinea pigs

The efficacy of endotracheal aerosolization of atropine sulfate for protection against soman (GD)-induced respiratory toxicity was investigated using microinstillation technique in guinea pigs. GD (841?mg/m³, 1.3 LCt₅₀ or 1121?mg/m³, 1.7 LCt₅₀) was aerosolized endotracheally to anesthetized male guinea pigs that were treated with atropine sulfate (5.0?mg/kg) 30 s postexposure by endotracheal microinstillation. Animals exposed to 841?mg/m³ and 1121?mg/m³GD resulted in 31 and 13% while treatment with atropine sulfate resulted in 100 and 50% survival, respectively. Cholinergic symptoms and increased body weight loss were reduced in atropine-treated animals compared to GD controls. Diminished pulse rate and blood O₂ saturation in GD-exposed animals returned to normal levels after atropine treatment. Increased cell death, total cell count and protein in the bronchoalveolar fluid (BALF) in GD-exposed animals returned to normal levels following atropine treatment. GD exposure increased glutathione and superoxide dismutase levels in BALF and that were reduced in animals treated with atropine. Respiratory parameters measured by whole-body barometric plethysmography revealed that treatment with atropine sulfate resulted in normalization of respiratory frequency, tidal volume, time of expiration, time of inspiration, end expiratory pause, pseudo lung resistance (Penh) and pause at 4 and 24?h post 841?mg/m³ GD exposure. Lung histopathology showed that atropine treatment reduced bronchial epithelial subepithelial inflammation and multifocal alveolar septal edema. These results suggest that endotracheal aerosolization of atropine sulfate protects against respiratory toxicity and lung injury induced by microinstillation inhalation exposure to lethal doses of GD.     

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and Guinea Pig

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and GuineaPig. CREASIA, D. A., THURMAN, J. D., WANNEMACHER, R. W., JR.,AND BUNNER, D. L. (1990). Fundam. Appl. Toxicol 14, 54–59.In this study, concentration-response parameters were determinedfor rats and guinea pigs systematically exposed to an aerosolof T-2 toxin. The LC50 for a 10-min exposure to T-2 toxin aerosolwas 0.02 mg T-2/liter air for rats and 0.21 mg T-2/liter airfor guinea pigs. Data from total T-2 deposition in rats andguinea pigs exposed to their respective LC50 aerosol concentrationgave an LD50 of 0.05 mg T-2/kg body weight for the rat and 0.4mg T-2/kg body weight for the guinea pig. These data show thatinhaled T-2 toxin is approximately 20 times more toxic to therat (0.05 mg T-2/kg body wt inhaled vs 1.0 mg T-2/kg body wtip) and at least twice as toxic to the guinea pig (0.4 mg T-2/kgbody wt inhaled vs 1-2 mg T-2/kg body wt ip) than ip administeredT-2 toxin. Histopathologic examination of major organs in boththe rat and guinea pig after respiratory exposure to T-2 toxinindicated that lesions were similar to those described aftersystemic administration of the toxin. Gross and microscopicalterations of respiratory tract tissue after T-2 aerosol exposurewere minimal and could not account for the increase in toxicity.     

Altered lung function in rats after subacute exposure to n-butyl isocyanate

The objectives of this study were to use pulmonary function tests, blood gas measurements and bronchoalveolar lung lavage (BAL) to characterize lesions in the respiratory tract of young adult male Wistar rats as a result of a 5-day exposure (6 h/day) to 0, 1.1, 6.2, 15 or 26 mg n-butyl isocyanate (n-BIC)/m³ air. Further objectives were to probe the diagnostic sensitivities of these procedures in comparison with more traditional evaluations (clinical observation, lung weight, histopathology). Measurements were performed during post-exposure weeks 2 and 5. Most rats exposed to 26 mg/m³ died or were sacrificed in a moribund state during post-exposure week 2. All other rats survived the exposure regimen. In rats exposed to 15 and 26 mg/m³ a significant decrease in body weight, laboured breathing, hypoactivity, nasal discharge, cyanosis, and hypothermia were observed. Pulmonary function measurements revealed increased total lung capacity (TLC) and residual volume (RV), decreased forced expiratory flow rates and quasistatic compliance in rats exposed to 26 mg/m³. At the end of the observation period rats exposed to 6.2 and 15 mg/m³ air were hyperresponsive to an acetylcholine bronchoprovocation aerosol. Arterial blood gas measurements revealed an arterial hypoxia and an increase in venous admixture, suggesting a severe mismatch of the ventilation-perfusion relationship, Biochemical and cellular components in BAL fluid (BALF) indicated a concentration dependent and protracted increase of polymorphonuclear leucocytes and further inflammatory parameters. In the 1.1 mg/m³ group BALF parameters were not significantly elevated. The major histopathological lesions of the lung were thickening of septa, emphysema, and intra-alveolar oedema in rats exposed to 26 mg/m³. Collectively, these results demonstrate obstructive and progressive lung disease with associated gas trapping and severe disturbance of the ventilation perfusion relationship which is considered to be the cause of delayed mortality. In terms of variability and sensitivity the increase in BALF parameters was most sensitive in indicating the diseased state of the lung.     

POSTTREATMENT WITH ETYA PROTECTS AGAINST PHOSGENE-INDUCED LUNG INJURY BY AMPLIFYING THE GLUTATHIONE TO LIPID PEROXIDATION RATIO

Exposure to phosgene has been shown to cause severe and life-threatening pulmonary edema. There is evidence that successful treatment of phosgene-induced acute lung injury may be related to increased antioxidant activity. Acetylenic acids such as 5,8,11,14-eicosatetraynoic acid (ETYA) have been shown to be effective in preventing pulmonary edema formation (PEF). In phosgene-exposed guinea pigs, we examined the effects of ETYA on PEF. Lipid peroxidation (thiobarbituric acid-reactive substance, TBARS) and total glutathione (GSH) were measured in lung tissue from isolated, buffer-perfused guinea pig lungs at 180 min after start of exposure. Guinea pigs were challenged with 175 mg/m³ (44 ppm) phosgene for 10 min (1750 mg min/m³). Five minutes after removal from the exposure chamber, guinea pigs were treated, ip, with 200 mu l of 100 mu M ETYA in ethanol (ETOH). Two hundred microliters of 50 mu M ETYA in ETOH was added to the 200 ml perfusate every 40 min beginning at 60 min after start of exposure (t = 0). There were four groups in this study: air-exposed, phosgene-exposed, phosgene + ETYA-posttreated, and air + ETYA-posttreated. Posttreatment with ETYA prevented GSH depletion, 2.7 +/- 0.5 mu mol/mg protein versus 1 +/- 0.2 mu mol/mg protein, for the untreated phosgene-exposed lungs (p less than or equal to.05). ETYA posttreatment also significantly decreased PEF (p less than or equal to.025), as measured by lung wet weight/dry weight ratio, 16.1 +/- 2.5 versus 8.5 +/- 1 for phosgene-exposed + ETYA-posttreated guinea pigs. Postexposure treatment with ETYA significantly increased the GSH to TBARS protection ratio, 12 +/- 2, compared with the phosgene-exposed group, 3.7 +/- 0.5 (p less than or equal to.05). In conclusion, ETYA posttreatment decreased PEF by increasing the GSH/TBARS protection ratio by functioning in an antioxidant-like capacity.     

Post-exposure treatment with nasal atropine methyl bromide protects against microinstillation inhalation exposure to sarin in guinea pigs

We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m³ sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarin exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.     

Inhalation toxicology of sodium sulfite aerosols in rats

Rats were exposed to well-characterized aerosols of sodium sulfite, at levels ranging from 0.1 to about 15 mg/m³ and particle sizes of about 1 μm (mass median aerodynamic diameter). The responses of rats to breathing these aerosols for 3 days were evaluated by measurements of glycoprotein secretion rates by cultured tracheal explants from these rats, by measurement of protein, DNA, and RNA levels of lung homogenates prepared from these rats, and by quantitation of wet to dry weight ratios of right apical lung lobes from these rats. Increased rates of glycoprotein secretion were observed for tracheae from rats exposed to 5 or to 15 mg/m³ of Na₂SO₃ aerosol, and increased wet to dry weight ratios of right apical lobes were also observed after exposure to these levels, as well as after exposure to 1 mg/m³ of Na₂SO₃ aerosol. Control experiments involving exposure to a sulfate (Na₂SO₄) aerosol at 15 mg/m³ indicated that the observed effects were indeed due to exposure to the sulfite moiety. Exposure to aerosols of sodium hydroxymethane sulfonate (the product of addition of formaldehyde to sodium sulfite) aerosols (5 mg/m³) elicited less response in these assays than did exposure to sodium sulfite aerosol at the same concentration. We conclude that exposure of rats to well-characterized 1-μm aerosols of sodium sulfite at concentrations equivalent to amounts of SO₂ of about 0.2 – 2.7 ppm results in responses of the rats that may be conveniently evaluated when sensitive enough toxicological indexes are quantitated.     

Multiple-Dose Chronic Inhalation Toxicity Study of Size-Separated Kaolin Refractory Ceramic Fiber in Male Fischer 344 Rats

Abstract

Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure an in an effort to define the dose-response, as a follow up to a maximum tolerated dose [30 mg/m³] study in rats (Mast et al., 1995), a multiple dose chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Four groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 3, 9, or 16 mg/m³(approximately 36, 91, and 162 fibers/cm³) of kaolin-based “size-selected” RCF fibers (approximately 1 µm in diameter and approximately 20 µm in length) for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and sacrificed (30 mo). Croups of 3–6 animals were sacrificed at 3, 6, 12, 18, and 24 mo to follow the progression of pulmonary lesions and to determine fiber lung burdens. Additional groups of 3–6 rats were removed from exposure at 3, 6, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. A dose-related increase in fiber lung burden was observed. Lung burdens at 24 mo ranged from 5.6 × 10⁴ to 27.8 × 10⁴ fibers/mg dry lung tissue. Significant increases in lung weights and lung to body weight ratios were seen in the high-dose group. Treatment-related lesions were restricted to the lungs. To some extent, all doses of RCF resulted in minimal to mild macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 12 mo of exposure. Interstitial fibrosis was observed at 12 mo in the 9 and 16 mg/m³ groups but not in the low-dose group at any time point. A minimal amount of focal pleural fibrosis was first observed at 12 mo in the 9 and 76 mg/m³ dose groups and progressed to a mild severity in the high-dose group by the end of the study. The incidence of pulmonary neoplasm's was well within the range typically reported in the male F344 rat. Neoplasm's (bronchoalveolar adenomas and carcinomas) were observed in all groups 10 mg/m³ (air control), 1 of 129 (0.8%); 3 mg/m³, 2 of 123 (1.6%); 9 mg/m³, 5 of 127 (3.9%); 16 mg/m³, 2 of 124 (1.6%)]. A single pleural mesothelioma was observed in an animal exposed to 9 mg/m³ of kaolin RCF. The results of this study suggest that the dose response for primary lung neoplasms is steep, while that for mesothelioma may not be.     

Aerosolized scopolamine protects against microinstillation inhalation toxicity to sarin in guinea pigs

Sarin is a volatile nerve agent that has been used in the Tokyo subway attack. Inhalation is predicted to be the major route of exposure if sarin is used in war or terrorism. Currently available treatments are limited for effective postexposure protection against sarin under mass casualty scenario. Nasal drug delivery is a potential treatment option for mass casualty under field conditions. We evaluated the efficacy of endotracheal administration of muscarinic antagonist scopolamine, a secretion blocker which effectively crosses the blood-brain barrier for protection against sarin inhalation toxicity. Age and weight matched male Hartley guinea pigs were exposed to 677.4?mg/m³ or 846.5?mg/?m³ (1.2?×?LCt₅₀) sarin by microinstillation inhalation exposure for 4?min. One minute later, the animals exposed to 846.5?mg/?m³ sarin were treated with endotracheally aerosolized scopolamine (0.25?mg/kg) and allowed to recover for 24?h for efficacy evaluation. The results showed that treatment with scopolamine increased the survival rate from 20% to 100% observed in untreated sarin-exposed animals. Behavioral symptoms of nerve agent toxicity including, convulsions and muscular tremors were reduced in sarin-exposed animals treated with scopolamine. Sarin-induced body weight loss, decreased blood O₂ saturation and pulse rate were returned to basal levels in scopolamine-treated animals. Increased bronchoalveolar lavage (BAL) cell death due to sarin exposure was returned to normal levels after treatment with scopolamine. Taken together, these data indicate that postexposure treatment with aerosolized scopolamine prevents respiratory toxicity and protects against lethal inhalation exposure to sarin in guinea pigs.     

Twenty‐eight‐day repeated inhalation toxicity study of nano‐sized lanthanum oxide in male sprague‐dawley rats

Although the use of lanthanum has increased in field of high‐tech industry worldwide, potential adverse effects to human health and to the environment are largely unknown. The present study aimed to investigate the potential toxicity of nano‐sized lanthanum oxide (La₂O₃) following repeated inhalation exposure in male Sprague‐Dawley rats. Male rats were exposed nose‐only to nano‐sized La₂O₃ for 28 days (5 days/week) at doses of 0, 0.5, 2.5, and 10 mg/m³. In the experimental period, we evaluated treatment‐related changes including clinical signs, body weight, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology findings. We also analyzed lanthanum distribution in the major organs and in the blood, bronchoalveolar lavage fluids (BALF), and oxidative stress in lung tissues. Lanthanum level was highest in lung tissues and showed a dose‐dependent relation. Alveolar proteinosis was observed in all treatment groups and was accompanied by an increase in lung weight; moreover, lung inflammation was observed in the 2.5 mg/m³ and higher dose groups and was accompanied by an increase in white blood cells. In the BALF, total cell counts including macrophages and neutrophils, lactate dehydrogenase, albumin, nitric oxide, and tumor necrosis factor‐alpha increased significantly in all treatment groups. Furthermore, these changes tended to deteriorate in the 10 mg/m³ group at the end of the recovery period. In the present experimental conditions, we found that the lowest‐observed‐adverse‐effect level of nano‐sized La₂O₃ was 0.5 mg/m³ in male rats, and the target organ was the lung. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1226–1240, 2017.     

Inhalation toxicity study of disk-shaped potassium octatitanate particles (Terracess TF) in rats following 90 days of aerosol exposure

Since fibrous particles such as asbestos and some man-made fibers (MMF) have been known to produce carcinogenic or fibrogenic effects, disk-shaped potassium octatitanate (POT) particles (trade name: Terracess TF) were manufactured as nonfibrous particles. A 90-day inhalation toxicity study of Terracess TF was performed to evaluate comparative inhalation toxicity of the disk shape with a fibrous shape that was previously evaluated. Four groups of 20 male and 15 female rats each were exposed to Terracess TF aerosols at concentrations of 0, 2, 10, or 50?mg/m³ for 90 days. Ten male and 10 female rats per group were sacrificed at 90 days of exposure. After 90 days of exposure, 5 male rats per group were sacrificed at 3 wk of recovery period and 4–5 male rats per group or 5 female rats per group were sacrificed at 15?wk of recovery for lung clearance and histopathology. The mass median aerodynamic equivalent diameter (MMAED) of the aerosols of test materials ranged from 2.5 to 2.9?μm. There were no test-substance-related adverse effects on clinical observations. At the end of the 90-day exposure, a slight increase in lung-to-body weight ratios was observed at 50?mg/m³ in male but not in female rats. However, lung weights were within normal limits after 3- or 15-wk recovery periods. Microscopically, inhaled Terracess TF particles were mostly phagocytized by free alveolar macrophages (AMs) in the alveolar airspaces and alveolar walls maintained normal structure at 2 and 10?mg/m³. At 50?mg/m³, some alveoli were distended and filled with aggregates of particle-laden AMs. The alveolar walls showed slight type II pneumocyte hyperplasia, but neither proliferative inflammation nor alveolar fibrosis was present at 50?mg/m³. The clearance half-times for Terracess TF were estimated to be in the order of 6 to 9?mo for the 50-mg/m³ group and 2 to 3?mo for the 10- and 2-mg/m³ groups. The lung responses and lung clearance rate were comparable to those of “nuisance” type dusts at these concentrations. Based on interpretation that aggregated particle-laden AMs in alveoli was considered to be an early histopathological sign of lung overloading, an effect level was considered to be 50?mg/m³ and no-observed-adverse-effect level (NOAEL) was 10?mg/m³. This experiment clearly demonstrated that particle morphology was considered to be an important factor to determine inhaled particle toxicity.     

Inhalation Toxicology of Fumed Dodecanediamine

Dodecanediamine (DDDA) is used in the production of specialty polymers. Exposure to this chemical was associated with dermal sensitization in pilot-plant workers, and the possibility that the chemical could produce dermal sensitization was confirmed in a guinea pig test. This property and its dermal irritative properties demonstrate the need to limit skin contact. The possibility of exposure via inhalation also exists. Although stable under ambient conditions, DDDA is processed at elevated temperatures where it may fume, forming a carbamate after reaction with atmospheric carbon dioxide. Some of the carbamate may be converted back to the diamine after hydrolysis in tissue. The rat was used to evaluate the effects of both acute and repeated exposure following inhalation. Fumed DDDA was found to be moderately toxic following a single 4-h exposure with lethality seen at concentrations of 680 mg/m³ or higher. Rats were then exposed to concentrations of either 0 (control), 11, 34, or 98 mg fumed DDDA/m³, 6 h/day, 5 days/wk for 2 wk. Mortality was seen at the highest concentrations, along with increased lung weights. In these rats, laryngeal and tracheal lesions consisting of acute necrosis and inflammation were seen, but surviving rats given a 14-day recovery period showed almost complete recovery. Tracheal and laryngeal lesions were not seen in rats exposed to either 11 or 34 mg/m³. Degenerative and necrotizing lesions were seen in the nasal regions, primarily the respiratory mucosa, of rats in all three treatment groups. The lesions were exposure related with regard to incidence and severity, but regeneration was seen following the recovery period. No evidence of systemic toxicity was seen. The dose-response characteristics of the nasal lesions and the sensitization potential suggest that workplace control levels of 0.1 mg/m³ should be sufficient to protect workers against the untoward effects of fumed DDDA.     

Changes in lung volumes and diffusing capacity in guinea pigs exposed to a combination of sulfur dioxide and submicron zinc oxide mixed in a humidified furnace

Male Charles River Hartley guinea pigs were exposed for 3 hr to zinc oxide (ZnO) aerosols alone (7.8 mg/m³) and to various concentrations of ZnO (0.8, 2.7, or 6.0 mg/m³) in combination with sulfur dioxide (SO₂). The ZnO aerosols (CMD 0.05 μm, σg 2.0) were generated by the condensation of supersaturated vapors and mixed with SO₂ in a water vapor-saturated furnace at 480°C. We evaluated ventilation, lung mechanics, lung volumes, diffusing capacity for carbon monoxide (DL_CO), and alveolar volume (VA) in anesthetized, tracheostomized animals after exposure to the aerosols. Breathing frequency, tidal volume, and pulmonary resistance and compliance were unchanged in all exposed groups. Exposure of animals to ZnO alone resulted in significant decrease in functional residual capacity (FRC) with only minimal changes in other lung volume subdivisions, DL_CO and VA. A dose response was induced in animals exposed to SO₂ and increasing concentrations of ZnO as shown by decreases in lung volumes, DL_CO and VA. In animals exposed to the lowest ZnO concentration (0.8 mg/m³), vital capacity (VC) was significantly lower while other lung volume parameters, DL_CO and VA, were unchanged compared to control values. As the concentration of ZnO was increased, as in the 6.0 mg/m³ ZnO group, all lung volume subdivisions, DL_CO and VA, were significantly decreased. Analysis of collected aerosols during the experiments indicated the presence of sulfate, sulfite, and adsorbed sulfur trioxide, all of which could induce bronchoconstriction in the guinea pig. The nature of the response in this study suggests a reaction in the periphery of the lungs indicating that the various sulfur species were carried into the lung parenchyma by the submicron ZnO particles. The decreased lung volumes, DL_CO and VA, indicate alveolar duct constriction probably with the involvement of pulmonary edema.     

Inhalation Toxicity of Methylglutaronitrile in Rats

Abstract

Methylglutaronitrile (MGN) is a high-boiling (263°C) solvent/intermediate used in the fiber industry. Twenty male rats per group were exposed nose-only to condensation aerosol/vapor concentrations of approximately either 5, 25, or 200 mg/m³ of MGN for 6 h/day, 5 days/week over a 4-week period. Ten rats/group were sacrificed one day after the final exposure and the remaining rats after a four-week recovery period. No effects were observed in clinical observations during the exposure period, but body-weight depression was observed in the 200 mg/m³ group. The 200 mg/m³ group showed minimal decreases in red blood cell count, hemoglobin, and hematocrit values accompanied by increases in reticulocytes. There were no other effects observed in clinical or pathologic evaluations in the study. A neurobehavioral battery of tests (including grip strength, functional observational battery, and motor activity tests) given at the end of the exposure and recovery periods showed no MGN effects. During the 4-week recovery, body weights in the 200 mg/m³ group returned to normal and the hematologic findings in all groups were normal. Based on the above findings of body weight depression at 200 mg/m³, the no-observed-adverse-effect level (NOAEL) for this study was considered to be 25 mg/m³.