Four-Week Inhalation Toxicity Study with Ludox Colloidal Silica in Rats: Pulmonary Cellular Responses

Four-Week Inhalation Toxicity Study with Ludox Colloidal Silicain Rats: Pulmonary Cellular Responses. WARHEIT, D. B., CARAKOSTAS,M. C, KELLY, D. P., AND HARTSKY, M. A. (1991). Fundam. Appl.Toxicol. 16, 590–601. This study was designed to complementa traditional subchronic inhalation toxicity study with Ludoxcolloidal silica. CD rats were exposed nose-only for 2 or 4weeks at concentrations of 0, 10, 50, and 150 mg/m³ Ludox (driedSiO₂). Additional groups of rats exposed for 4 weeks were givena 3-month recovery period. Following exposure and/or recovery,fluids and cells were recovered from the lungs by bronchoalveolarlavage (BAL) and measured for cellular and biochemical parameters.Additional groups of animals were processed for cell labelingstudies or lung deposition studies. Inhaled doses of Ludox colloidalsilica were measured after 4-week exposures and were found tobe 489 µg/lung (10 mg/m³ group), 2418 µg/lung (50mg/m³), and 7378 µg/lung (150 mg/m³), respectively. Resultsshowed that exposures to 150 mg/m³ Ludox for 2 or 4 weeks producedpulmonary inflammation along with increases in BAL protein,LDH, and alkaline phosphatase values (p<0.05) and reducedmacrophage phagocytosis. Inflammatory responses, evidenced byincreased numbers of neutrophils, were also measured in thelungs of the 50 mg/m³ group following 2 and/or 4 weeks of exposure.Most biochemical parameters for all groups returned to controlvalues following a 3-month recovery period. Autoradiographicstudies demonstrated that the labeling indices of terminal bronchiolarand lung parenchymal cells were generally increased in the 50and 150 mg/m³ groups after 2 and 4 weeks of exposure but, withone exception, returned to normal levels following a 3-monthpostexposure period. No significant alterations in any measuredparameters were detected in rats exposed to 10 mg/m³ Ludox atany time postexposure. The determination of a no-observable-effectlevel (NOEL) of 10 mg/m³ was consistent with results obtainedby conventional toxicology methods and affirms the utility ofthese biochemical, cellular, and autoradiographic techniquesfor providing a predictive screen to assess the toxicity ofinhaled particles.     

Assessment of Toxicity of o-Nitrochlorobenzene in Rats following a 4-Week Inhalation Exposure

Assessment of Toxicity of o-Nitrochlorobenzene in Rats followinga 4-Week Inhalation Exposure. NAIR, R.S., JOHANNSEN, F.R., LEVINSKAS,G.J., AND TERRILL, J.B. (1986). Fundam. Appl. Toxicol. 7, 609-614.o-Nitrochlorobenzene (ONCB) is a chemical intermediate usedfor the synthesis of various industrial chemicals. To evaluatethe subchronic toxicity of this compound, three groups of 15male and 15 female Sprague-Dawley rats were exposed to ONCBvapor 6 hr/day, 5 days/week for 4 weeks at target concentrationsof 10, 30, or 60 mg/m³. A control group of 15 animals/sex wasexposed to room air in a separate inhalation chamber. Concentrationsof ONCB in the chambers were determined at least three timesa day using a uv spectrophotometer. Parameters monitored inthis study included observation for signs of toxicity, bodyweights, ophthalmoscopic exam, hematology, and clinical chemistry.At necropsy, selected organ weights were recorded and over 35tissues/animal were examined microscopically for all controland high-exposure level animals. No mortality was observed inthis study. Mean body weights of all groups were comparableto controls. Animals exposed to the mid and high concentrationsof ONCB showed a significant increase in blood methemoglobinand a significant decrease in hemoglobin, hematocrit, and redblood cell counts. Spleen and liver weights (absolute and relativeto body weight) were significantly increased for these two groups.Microscopic changes, observed only in the spleen, included increaseddegree of extramedullary hematopoiesis and hemosiderosis. Thesedata suggest that the toxicity of ONCB is comparable to thatof its structural analog, p-nitrochlorobenzene. Thus these twocompounds should have similar workplace exposure limits.     

Pulmonary Response to Toner upon Chronic Inhalation Exposure in Rats

Pulmonary Response to Toner upon Chronic Inhalation Exposurein Rats. MUHLE, H., BELLMANN, B., CREUTZENBERG, O., DASENBROCK,C., ERNST, H., KILPPER, R., MACKENZIE, J. C., MORROW, P., MOHR,U., TAKENAKA, S., AND MERMELSTEIN, R., Fundam. Appl. Toxicol.17, 280–299. A chronic inhalation study of a test tonerwas conducted by exposure of groups of F-344 rats for 6 hr/day,5 days/week for 24 months The test toner was a special Xerox9000 type xerographic toner, enriched in respirable-sized particlescompared to commercial toner, such that it was about 35% respirableaccording to the ACGlH criteria. The target test aerosol exposureconcentrations were 0, 1.0 (low), 4.0 (medium), and 16.0 (high)mg/m³. Titamum dioxide (5 mg/m³) and crystalline silicon dioxide(1 mg/m³), used as negative and pasitive controls for fibrogenicity,were also evaluated. Inhalation of the test toner or the controlmaterials showed no signs of overt toxicity. Body weight, clinicalchemistry values, food consumption, and organ weights were normalin the toner- and TiO₂-exposed groups, except for a 40% increasein lung weight in the toner highexposure group. All of the changesin the toner-exposed groups were restricted to the lungs orassociated lymph nodes. A chronic inflammatory response wasevident from the bronchoalveolar lavage parameters for the tonerhigh-exposure group. The incidence of primary lung tumors wascomparable among the three toner-exposed groups and the TiO²-exposed,and air-only controls, as well as consistent with historicalbackground levels A mild to moderate degree of lung fibrosiswas observed in 92% of the rats in the toner high-exposure group,and a minimal to mild degree of fibrosis was noted in 22% ofthe animals in the toner high-exposure group. The pulmonarychanges in the toner high-exposure group were smaller in magnitudethan those found in the crystalline silica-exposed group. Thecomparative fibrogenic potency of TiO², toner, and SiO² wasestimated to be 1:5:418 using a dasimetric model and assuminga common mechanistic basis. There were no pulmonary changesof any type at the toncr low-exposure level, which is most relevantin regard to potential human exposures The lung alterationsin the toner high-exposure group are interpreted in terms of"lung overloading," a generic response of the respiratory systemto saturation of its detoxification capacity. The maximum tolerateddose (MTD) criterion was met at the toner high (16 mg/m³)-exposurelevel.     

Subschronic Silica Exposure Enhances Respiratory Defense Mechanisms and the Pulmonary Clearance of Listeria Monocytogenes in Rats

Both Listeria monocytogenes infection and silica exposure have been shown to significantly alter immune responses. In this study, we evaluated the effect of preexposure to silica on lung defense mechanisms using a rat pulmonary L. monocytogenes infection model. Male Sprague-Dawley rats were instilled intratracheally with saline (vehicle control) or silica using either an acute treatment regimen (5 mg/kg; 3 days) or a subchronic treatment protocol (80 mg/kg; 35 days). At 3 or 35 days after silica instillation, the rats were inoculated intratracheally with either ~5000 or 500,000 L. monocytogenes. At 3, 5, and 7 days postinfection, the left lung was removed, homogenized, and cultured on brain heart infusion agar at 37°C. The numbers of viable L. monocytogenes were counted after an overnight incubation. Bronchoalveolar lavage (BAL) was performed on the right lungs, and BAL cell differentials, acellular lactate dehydrogenase (LDH) activity and albumin content were determined. Alveolar macrophage (AM) chemiluminescence (CL) and phagocytosis were assessed as a measure of macrophage function. Lung-associated lymph nodes were removed, and lymphocytes were recovered and differentiated. Preexposure to silica significantly increased the pulmonary clearance of L. monocytogenes as compared to saline controls. Exposure to silica caused significant increases in BAL neutrophils, LDH and albumin, and lymph-nodal T cells and natural killer (NK) cells in infected and noninfected rats. CL and phagocytosis were also elevated in silica-treated rats. In summary, the results demonstrated that exposure of rats to silica enhanced pulmonary immune responses, as evidenced by increases in neutrophils, NK cells, T lymphocytes, and macrophage activation. These elevations in pulmonary immune response are likely responsible for the increase in pulmonary clearance of L. monocytogenes observed with preexposure to silica.     

2-Week Inhalation Study of N-Monomethylformamide in Rats

2-Week Inhalation Study of yV-Monomethylformamide in Rats. KENNEDY,G. L., JR., FERENZ, R. L., BURGESS, B. A., AND STULA, E. F.(1990). Fundam. Appl. Toxicol. 14, 810–816. N-Monomethylformamide(MMF) is a chemical intermediate with potential for inhalationexposure in humans. Human exposures to MMF have occurred incancer chemotherapy but have been limited due to liver damage.To assess the toxicity of MMF, groups of 15 male rats each wereexposed by nose-only inhalation, 6 hr/day, 5 days/week, for2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Fiverats per group were killed following the 10th exposure, fivewere killed after a 14-day postexposure recovery period, andfive rats were used to determine urinary MMF excretion. Parametersinvestigated were clinical observations and body weights, clinicalpathology, and gross and microscopic pathology including organweights. Liver damage occurred in rats exposed to either 130or 400 ppm. This was detected both by increases in serum enzymeactivity indicative of liver injury and by microscopic changesin the liver. The changes were more severe in the 400-ppm ratsand were partially reversible. Other organs were not adverselyaffected by inhalation of MMF. The amount of MMF excreted inthe urine was dependent on the exposure concentration and MMFwas present 14 days postexposure at the higher exposure levels.The no-observed-effect level under the conditions of this experimentwas 50 ppm.     

Pulmonary Effects and Clearance After Long-Term Inhalation of Potassium Octatitanate Whiskers in Rats

The pulmonary effects of long-term inhalation of potassium octatitanate whisker (PT1), one of the durable man-made fibers (MMFs), were examined in rats. Male Wistar rats were exposed to PT1 by inhalation for 6 h/day, 5 days/wk for 1 yr. The daily average exposure concentration of PT1 aerosol was 2.2 ± 0.7 mg/m³ (111 ± 34 fiber/ml) during the exposure. Rats were sacrificed at 3 days, 6 mo, and 12 mo after 1 yr of inhalation exposure. The amount of deposited PT1 in rat lungs (lung burden) was 2.4 ± 0.7 mg and the deposition fraction was 7.2% at 3 days after 1 yr. The clearance of inhaled PT1 after 1-yr inhalation was prolonged so that the biological half-life time (BHT) was difficult to estimate. The histopathological findings showed that mild fibrotic changes were observed around the macrophages that had engulfed the PT1 in the 3-day, 6-mo, and 12-mo rat sacrifice groups. As for pulmonary tumors, no malignant tumors were observed, although 2 adenomas at 6 mo and 1 adenoma and 1 squamous metaplasia at 12 mo after the exposure were found in the rat lungs.     

Pulmonary Function and Particle Deposition and Clearance in Rats After a 90-Day Exposure to Shale-Oil-Derived Jet Fuel JP-4

Abstract

A computerized, semiautomated plethysmograph system with a frequency response flat to 50 Hz was developed for pulmonary function evaluations in the rat. Before measuring the pulmonary effects of a 90-d exposure to shale-oil-derived JP-4, the sensitivity of this system was evaluated using papain-induced emphysema and bleomycin-induced fibrosis. The effects from these pulmonary insults were evaluated in tests of lung volumes, dynamic resistance and compliance, quasistatic compliance, partial and full forced vital capacities, carbon monoxide (CO) diffusion capacity, and closing volume. In addition, particle deposition and clearance were evaluated using ⁵¹Cr -labeled polystyrene latex microspheres. lntratracheally instilled bleomcyin (7 IU/kg) induced patchy interstitial fibrosis and generated a pattern of restrictive lung disease with significant changes in lung volumes and flow rates and significant differences in particle deposition and clearance. lntratracheally instilled papain (300 IU/kg) induced panlobular emphysema and generated a pattern of obstructive lung disease with significant changes in lung volumes, compliance, flow rates, gas distribution, CO diffusion, and mean linear intercept but showed no effects on particle deposition or clearance. Whereas previous reports found other hydrocarbon fuel exposures induced nasal inflammation and pulmonary irritation, a 90-d continuous exposure to 1000 mg/m³ shale-oil-derived JP-4 produced no significant effect histopathologically or in any measured pulmonary function, deposition, or clearance parameter.     

Dimethylethanolamine: Acute, 2-Week, and 13-Week Inhalation Toxicity Studies in Rats

Dimethylethanolamine (DMEA) is a volatile, water-soluble aminethat has applications in the chemical and pharmaceutical industries.These studies evaluated the acute and subchronic inhalationtoxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEAvapor resulted in an LC5O value (95% confidence limits) of 1641(862–3125)ppm. Clinical signs of nasal and ocular irritation, respiratorydistress, and body weight loss were observed in rats exposedto 1668 ppm DMEA and higher. In the 2-week study, F-344 ratsexposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) duringan 11-day period also exhibited signs of respiratory and ocularirritation (except the 98 ppm group). All animals of the 586ppm group and 4 of 15 male rats of the 288 ppm group died. Bodyweight values for the 288 ppm group were reduced to about 75%of preexposure values, while the 98 ppm group gained 35% lessweight than controls. Statistically significant differencesin clinical pathology parameters (288 ppm group) and in organweight values (288 and 98 ppm groups) probably resulted fromthe decreased food consumption and not from specific targetorgan toxicity. In the groups evaluated histologically (the98 and 288 ppm groups) the eye and nasal mucosa were the primarytarget organs. In the 13-week subchronic study, F-344 rats wereexposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/weekfor 13 weeks. The principal exposure-related changes were transientcorneal opacity in the 24 and 76 ppm groups; decreased bodyweight gain for the 76 ppm group; and histopathologic lesionsof the respiratory and olfactory epithelium of the anteriornasal cavity of the 76 ppm group and of the eye of several 76ppm group females. Rats maintained for a 5-week recovery periodonly exhibited histological lesions of the nasal tissue, withthe lesions being decreased in incidence and severity. DMEAacts primarily as an ocular and upper respiratory tract irritantand toxicant at vapor concentrations of 76 ppm, while 24 ppmor less produced no biologically significant toxicity in rats.Thus, 24 ppm was considered to be the no-observable-effect level.     

The Immunotoxicity of Three Nickel Compounds following 13-Week Inhalation Exposure in the Mouse

The Immunotoxicity of Three Nickel Compounds following 13-WeekInhalation Exposure in the Mouse. HALEY, P. J. SHOPP, G. M.,BENSON, J. M, CHENG, Y.-S., BICE, D. E., LUSTER, M. I., DUNNICK,J. K., AND HOBBS, C. H. (1990). Fundam. Appl. Toxicol 15, 476–487.Groups of B6C3F₁, mice were exposed to aerosols of nickel subsulfide(Ni₃S₂), nickel oxide (NiO), or nickel sulfate hexahydrate (NiSO₄6H₂O)6 hr/day, 5 days per week for 65 days to determine the immunotoxicityof these compounds. Exposure concentrations were 0.11, 0.45,and 1.8 mg Ni/m³ for Ni₃S₂, 0.47, 2.0, and 7.9 mg Ni/m³ forNiO; and 0.027, 0.11, and 0.45 mg Ni/m³ for NiSO₄. Thymic weightswere decreased only in mice exposed to 1.8 mg Ni/m³ Ni₃S₂. Increasednumbers of lung-associated lymph nodes (LALN), but not spleennucleated cells, were seen with all compounds. Nucleated cellsin lavage samples were increased in mice exposed to the highestconcentrations of NiSO₄ and NiO and to 0.45 and 1.8 mg Ni/m³Ni₃S₂. Increased antibody-forming cells (AFC) were seen in LALNof mice exposed to 2.0 and 7.9 mg Ni/m³ NiO and 1.8 mg Ni/m³Ni₃S₂. Decreased AFC/10⁶ spleen cells were observed in miceexposed to NiO, and decreased AFC/spleen were seen for miceexposed to 1.8 mg Ni/m³ Ni₃S₂. Only mice exposed to 1.8 mg Ni/m³Ni₃S₂ had a decrease in mixed lymphocyte response. All concentrationsof NiO resulted in decreases in alveolar macrophage phagocyticactivity, as did 0.45 and 1.8 mg Ni/m³ Ni₃S₂. None of the nickelcompounds affected the phagocytic activity of peritoneal macro-phages.Only 1.8 mg Ni/m³ Ni₃S₂ caused a decrease in spleen naturalkiller cell activity. Results indicate that inhalation exposureof mice to nickel can result in varying effects on the immunesystem, depending on dose and physicochemical form of the nickelcompound. These nickel-induced changes may contribute to significantimmunodysfunction.     

Subchronic Toxicity of 4-Vinylcyclohexene in Rats and Mice by Inhalation Exposure

This study was conducted to evaluate the subchronic toxicityof 4-vinylcyclohexene (VCH). Male and female Sprague–Dawleyrats and B6C3F₁ mice were exposed by inhalation to VCH 6 hr/day, 5 days/week for 13 weeks. Rats were exposed to 0, 250,1000, or 1500 ppm, and mice were exposed to 0, 50, 250, or 1000ppm. In addition, another group of rats and mice was exposedto 1000 ppm butadiene so that a comparison could be made betweenthe two compounds. Exposure to 1000 ppm VCH resulted in deathsof all male mice and 5/10 female mice on Test Days 11 or 12.Three additional female mice exposed to 1000 ppm VCH died priorto study completion. The most notable compound-related clinicalsign was lethargy observed in the 1500 ppm VCH-exposed ratsand 1000 ppm VCH-exposed mice. Male rats exposed to 1500 ppmVCH had significantly lower body weights compared to controls,and male and female rats in the 1500 ppm group had signifi cantlylower body weight gains. None of the VCH-exposed animals orbutadiene-exposed rats showed any compound-related hemato logicaleffects. However, mice exposed to 1000 ppm butadiene exhibitedmild macrocytic anemia. Clinical chemistry evaluation and urinalysisshowed no compound-related effects in rats exposed to eitherVCH or butadiene. Male and female rats exposed to 1000 or 1500ppm VCH or 1000 ppm butadiene had increased absolute and/orrelative liver weights, and male rats in these same exposuregroups had increased relative kidney weights. Microscopically,in creased accumulation of hyaline droplets was observed inthe kid neys of male rats from all VCH exposure groups. Althoughcompound–related, the droplets were not accompanied bycytotoxicity. In mice, the most notable adverse histopathologicaleffect was ovarian atrophy in females exposed to 1000 ppm VCHor 1000 ppm butadiene. The atrophy was slightly more severein the VCH exposed females than in the butadiene–exposedfemales. There were no other compound–related pathologicaleffects in male or female mice exposed to VCH. Additionally,butadiene–exposed male mice had decreased testicular weights,accompanied by slight testicular degeneration and atrophy. ForVCH exposure, the no–observed-adverse–effect–levelis 1000 ppm for rats based on leth argy and lowered body weightsand 250 ppm for mice based on mortality and ovarian atrophy.     

Phenyl Isocyanate-Induced Asthma in Rats Following a 2-Week Exposure Period

This study was conducted to assess the toxic effects of repeatedinhalation exposures to phenyl isocyanate vapor in male Wistarrats. Rats were exposed to design concentrations of 0, 1, 4,7, or 10 mg/m³ phenyl isocyanate air for 2 weeks (6 hr/day,5 days/week). The rats were assessed for normal toxicologicparameters, and pulmonary function tests, blood gas measurements,and analysis of bronchoalveolar lavage fluid (BALF) parameterswere utilized shortly after exposures as well as 2 months postexposure.The results indicated that rats exposed to 7 and 10 mg/m³ experienceddecreased body weights, hypoactivity, hypothermia, signs ofrespiratory tract irritation, delayed onset of mortality, andchanges in organweights. In addition, pulmonary function testsdemonstrated decreased forced expiratory flow rates and quasistaticlung compliance. Arterial blood gases showed an arterial hypoxemiaand changes consistent with a pronounced venous-admixture-likeperfusion, suggesting severe mismatch of the ventilation/perfusionrelationship. Delayed onset of mortality appeared to be associatedwith respiratory acidosis and hypoxernia. Biochemical and cellularcomponents in BALF complemented the results of the functionalalterations. Remarkable changes were indicated by increasedactivities of the BALF parameters, -GPT, protein, and sialicacid. Histopathological findings provided evidence of increasedsecretory cell activity and a concentration-dependent increasein goblet cell hyperplasia at concentrations of 4 mg/m³ andabove. In rats exposed to 7 mg/m³ further findings consistedof intraluminal inflammation of airways, hypertrophia of bronchialsmooth muscle, epithelial desquamation, and eosinophilia ofthe airways. A complete regression of morphological lesionswas not found in the animals exposed to 4 mg/m³ and above atthe 2-month postexposure time period. In conclusion, the damageto the airways comprise most of the features characteristicof chronic airway inflammation or asthma.     

Nasal Toxicity of Manganese Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure

Growing evidence suggests that nasal deposition and transport along the olfactory nerve represents a route by which inhaled manganese and certain other metals are delivered to the rodent brain. The toxicological significance of olfactory transport of manganese remains poorly defined. In rats, repeated intranasal instillation of manganese chloride results in injury to the olfactory epithelium and neurotoxicity as evidenced by increased glial fibrillary acidic protein (GFAP) concentrations in olfactory bulb astrocytes. The purpose of the present study was to further characterize the nasal toxicity of manganese sulfate (MnSO₄) and manganese phosphate (as hureaulite) in young adult male rats following subchronic (90-day) exposure to air, MnSO₄ (0.01, 0.1, and 0.5 mg Mn/m³), or hureaulite (0.1 mg Mn/m³). Nasal pathology, brain GFAP levels, and brain manganese concentrations were assessed immediately following the end of the 90-day exposure and 45 days thereafter. Elevated end-of-exposure olfactory bulb, striatum, and cerebellum manganese concentrations were observed following MnSO₄ exposure to ≥0.01, ≥0.1, and 0.5 mg Mn/m³, respectively. Exposure to MnSO₄ or hureaulite did not affect olfactory bulb, cerebellar, or striatal GFAP concentrations. Exposure to MnSO₄ (0.5 mg Mn/m³) was also associated with reversible inflammation within the nasal respiratory epithelium, while the olfactory epithelium was unaffected by manganese inhalation. These results confirm that high-dose manganese inhalation can result in nasal toxicity (irritation) and increased delivery of manganese to the brain; however, we could not confirm that manganese inhalation would result in altered brain GFAP concentrations.     

Isopropanol 13-Week Vapor Inhalation Study in Rats and Mice with Neurotoxicity Evaluation in Rats

This study was conducted to evaluate the possible subchronictoxicity as well as neurobehavioral effects of isopropanol,a widely used industrial and commercial solvent. Five groups,each containing 10 Fischer 344 rats/sex and 10 CD-I mice/sex,were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanolvapor at concentrations of 0 (control), 100, 500, 1500, or 5000ppm. An additional 15 rats/sex were assigned to the 0, 500,1500, and 5000 ppm groups for assessment of neurobehavioralfunction. No exposure-related mortalities occurred during thestudy. The narcotic effects of isopropanol were noted only duringexposures at 1500 and 5000 ppm. These signs, noted during exposures,were typically absent following exposures. The only clinicalsigns observed following exposures included swollen perioculartissue, perinasal encrustation, and ataxia for rats of the 5000ppm group. Neurobehavioral evaluations indicated no changesin any of the parameters of the functional observational battery;however, increased motor activity for female rats in the 5000ppm group was noted at Weeks 9 and 13. Decreases in body weightand body weight gain were observed for rats of the 5000 ppmgroup at the end of the first week of exposure. During the remainingweeks, increases in body weight and/or body weight gain wereobserved for rats of the 1500 and 5000 ppm groups. No exposure-relatedeffects on body weight were noted for male mice; however, increasedbody weight and body weight gain were observed for female miceof the 5000 ppm group. Increases or decreases in food and waterconsumption generally corresponded to changes in body weightand body weight gain. Various changes in clinical pathologyparameters were observed for rats and female mice of the 5000ppm group. The only organ weight effect noted was an increasedrelative liver weight in both sexes of rats of and female miceof the 5000 ppm group. At necropsy, three were no gross lesionsdetermined to be exposure related. Furthermore, the only microscopicchange observed was hyaline droplets within the kidneys of allmale rats (including controls). The size and frequency of thehyaline droplets were increased for the isopropanol exposuregroups compared to the control group. These differences werenot clearly concentration related, although this microscopicchange was most pronouced in the high-concentration group. Neuropatholo0gicexamination revealed no exposure-related lesions in the centralor peripheral nervous system of exposed rats. Thus, repeatedexposures to isopropanol for 13 weeks produced toxic effctsonly at the highest concentration and a kidney change in malerats of unknown biological significance.     

Lung Response to Ultrafine Kevlar Aramind Synthetic Fibrills Following 2-Year Inhalation Exposure in Rats

Lung Response to Ultrafine Kevlar Aramid Synthetic Fibrils following2-Year Inhalation Exposure in Rats. LEE K. P., KELLY D.P. O'NEALF. O., STADLER, J. C., AND KENNEDY G. L., JR (1988). Fundam.Appl. Toxicol. 11, 1-20. Four groups of 100 male and 100 femalerats were exposed to ultrafine Kevlar fibrils at concentrationsof 0, 2.5,25, and 100 fibrils/cc for 6 hr/day, 5 days/week for2 years. One group was exposed to 400 fibrils/cc for 1 yearand allowed to recover for 1 year. At 2.5 fibrils/cc, the lungshad normal alveolar architecture with a few dust-laden macrophages(dust cell response) in the alveolar airspaces. At 25 fibrils/cc,the lungs showed a dust cell response, slight Type II pneumocytehyperplasia, alveolar bronchiolariation, and a negligible amountof collagenized fibrosis in the alveolar duct region. At 100fibrils/cc, the same pulmonary responses were seen as at 25fibrilsol;cc. In addition, cystic keratinizing squa- mous cellcarcinoma (CKSCC) was found in 4 female rats, but not in malerats. Female rats had more prominent foamy alveolar macrophages,holesterol granulomas, and alveolar bronchio-larization. Thesepulmonary lesions were related to the development of CKSCC.The lung tumors were derived from metaplastic squamous cellsin areas of alveolar bronchiolarization. At 400 fibrils/cc following1 year of recovery, the lung dust content, average fiber length,and the pulmonary lesions were markedly reduced, but slightcentriacinar emphysema and minimal collagenized fibrosis werefound in the alveolar duct region. One male and 6 female ratsdeveloped CKSCC. The lung tumors were a unique type of experimentallyinduced tumors in the rats and have not been seen as spontaneoustumors in man or animals. Therefore, the relevance of this typeof lung tumor to the human situation is minimal.     

Chlorpyrifos: A 13-Week Nose-Only Vapor Inhalation Study in Fischer 344 Rats

Fischer 344 rats were exposed by the nose-only inhalation routeto chlorpyrifos vapors at concentrations of 0, 5.2, 10.3, or20.6 ppb, 6 hr/day, 5 days/week for 13 weeks. The exposure concentrationswere limited by the low vapor pressure of chlorpyrifos (theoreticalmaximum vapor concentration of 25 ppb at 25?C). No treatment-relatedsigns of toxicity or changes in body weights were detected duringthe course of the study. Unnalysis, hematology, clinical chemistry,organ weights, gross pathologic, and histopathologic evaluationswere performed at the end of the study with no treatment-relatedeffects observed. In addition, no differences from controlswere noted in plasma, red blood cell, or brain cholinesteraseactivities. The results of this study indicate that the no-observed-effectlevel for chlorpyrifos vapor was the highest attainable concentration,20.6 ppb, in male and female Fischer 344 rats.     

Biopersistence of Graphite Whiskers Deposited in Rat Lungs by 4-Week Inhalation

Rats were exposed to a new graphite whisker for 4 wk by inhalation. Mass and fiber concentrations were 8.3 ± 2.2 mg/m 3 and 151.7 ± 78.8 fibers (F)/ml, respectively, and mass median aerodynamic diameter was 3.0 µm. Geometric mean sizes of the original whiskers were 0.86 µm diameter and 6.8 µm length. Size distributions, numbers, and mass of deposited whiskers in rat lungs were measured at 4 days, 7 mo, and 12 mo after the end of the exposure. Lungs including the whiskers were digested with acids by microwaves, then filtered onto polycarbonate filters. The number of whiskers on the filters was counted and sizes were measured based on scanning electron microphotos, and the mass was analyzed by an x-ray diffractometer. Change in the number of whiskers in the lung was expressed as an exponential decay with time, and the longer whiskers (>20 µm) tended to remain selectively in the lung after the 12-mo clearance. Mass of graphite whisker also decreased exponentially. Count median diameters and lengths (CMDs and CMLs) decreased gradually during clearance time, although CMDs did not decrease linearly. Morphological change of this whisker was very unique and characteristic; that is, the surface of the whiskers peeled away in the lung as a result of their stratified crystalline structure.     

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation ToxicityStudy in Rats and Rabbits. Landry, T.D., Gushow, T.S. and Yano,B.L. (1983). Fundam. Appl. Toxicol. 3:627–630. Fischer344 rats (10/sex/exposure concentration) and New Zealand Whiterabbits (7/sex/exposure concentration) were exposed to 0, 300,1000, or 3000 ppm (0, 1.09, 3.62, or 10.9 mg/L) of propyleneglycol monomethyl ether (PGME) for 6 hr/da, 5 da/wk, for 13weeks. Minimal effects were observed in animals exposed to 3000ppm. Indications of a transient central nervous system depressionwere observed in rats and rabbits exposed to 3000 ppm. Therewere also small increases (6 to 8%) in mean relative liver weightsof 3000 ppm exposed male and female rats relative to controls.Minimal histologic effects were observed in the livers of 3000ppm exposed female rats. These were suggestive of hepatocellularhypertrophy but were without evidence of degenerative changes.There was an increase in the urinary pH of male rats exposedto 3000 ppm PGME for 4 weeks, but this was not evident after12 weeks of exposure. There was no indication of histopathologicaleffects in the kidneys of either species, and there were nohematological effects. No treatment-related effects were foundin either rats or rabbits exposed to 300 or 1000 ppm.     

2,4-Pentanedione: 9-Day and 14-Week Vapor Inhalation Studies in Fischer-344 Rats

2,4-Pentanedione: 9-Day and 14-Week Vapor Inhalation Studiesin Fischer-344 Rats. DODD, D.E., GARMAN, R.H., PRITTS, I.M.,TROUP, C.M., SNELLINGS, W.M, AND BALLANTYNE, B. (1986). Fundam.Appl. Toxicol. 7, 329–339. Fischer-344 rats, in groupsof 10 males and 10 females, were exposed for 9 days (6 hr/day)to 2,4-pentanedione (2,4-PD) vapor at mean concentrations of805, 418, 197, and 0 (control) ppm. No deaths occurred, andthe only adverse signs were of sensory irritation (partial closureof eyelids, periocular and perioral wetness) at 805 ppm. Alsoat 805 ppm were decreased body and organ weights, lymphocytosis,and moderate inflammation of the nasal mucosa. At 418 ppm therewas a decrease in body weight gain and mild inflammation ofthe nasal mucosa. Apart from minimal nasal mucosa] inflammation,there were no effects at 197 ppm. In the subchronic (14-week)study, rats were exposed (6 hr/day; 5 days/week) to 650, 307,101, and 0 (control) ppm of 2,4-PD vapor, using groups containing20 males and 20 females, with half being sacrificed at the endof the exposure period and the remainder kept for a 4-week postexposurerecovery period. An additional 10 males were added to the 650and 0 ppm groups for glutaraldehyde perfusion and subsequentelectron microscopic examination of sciatic nerves. At 650 ppm,all females and 10 of 30 males died between the second and sixthweeks of exposure. These animals had acute degenerative changesin the deep cerebellar nuclei, vestibular nuclei and corporastriata, and acute lymphoid degeneration in the thymus. Sevenof 15 male survivors of the 650 ppm group (combined 14-weekand recovery sacrifices) had gliosis and malacia in the samebrain regions, minimal squamous metaplasia in the nasal mucosa,decreased body and organ weights, lymphocytosis, and minor alterationsin serum and urine chemistries. No ultrastructural evidenceof peripheral neuropathy was observed. Except for central neuropathy,many of the adverse effects at 650 ppm were less marked in the4-week recovery animals. No deaths occurred at 307 ppm, butfemales had slightly decreased body weight gains, and in bothsexes there were minor alterations in hematology, serum chemistry,and urinalysis parameters, which were not present in the 4-weekrecovery animals. Rats exposed to 101 ppm showed no differencesfrom the control rats. Subchronic exposure to 650 ppm of 2,4-PDvapor causes serious adverse biological effects. Under thesestudy conditions, the minimum-effects concentration was 307ppm, and the no-adverse effects concentration was 101 ppm.     

Dipropylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Dipropylene Glycol Monomethyl Ether. A 13-Week Inhalation Studyin Rats and Rabbits. LANDRY, T. D., AND YANO, B. L. (1984).Fundam. Appl. Toxicol. 4, 612–617. Fischer 344 rats (10/sex/exposureconcentration) and New Zealand White rabbits (7/sex/exposureconcentration) were exposed to 0, 15, 50, or 200 ppm (0, 91,303, or 1212 mg/m3) of dipropylene glycol monomethyl ether (DPGME)for 6 hr/day, 5 days/week for 13 weeks. Criteria of responseincluded general observations, body weights, clinical chemistry,hematology, urinalyses (rats only), necropsy, organ weights,and histopathology. There were no effects attributed to exposureto DPGME at any exposure concentration in either male or femalerats or rabbits. The highest concentration tested (200 ppm)was approximately 40% of a saturated DPGME atmosphere. Basedon the low vapor pressure of DPGME, and results in this 13-weekstudy, DPGME appears to have a low subchronic vapor inhalationtoxicity hazard.