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.     

Acute Lung Injury Following Inhalation Exposure to Nerve Agent VX in Guinea Pigs

A microinstillation technique of inhalation exposure was utilized to assess lung injury following chemical warfare nerve agent VX [methylphosphonothioic acid S-(2-[bis(1-methylethyl)amino]ethyl) O-ethyl ester] exposure in guinea pigs. Animals were anesthetized using Telazol-meditomidine, gently intubated, and VX was aerosolized using a microcatheter placed 2 cm above the bifurcation of the trachea. Different doses (50.4 μg/m³, 70.4 μ g/m^m3, 90.4 μg/m^m3) of VX were administered at 40 pulses/min for 5 min. Dosing of VX was calculated by the volume of aerosol produced per 200 pulses and diluting the agent accordingly. Although the survival rate of animals exposed to different doses of VX was similar to the controls, nearly a 20% weight reduction was observed in exposed animals. After 24 h of recovery, the animals were euthanized and bronchoalveolar lavage (BAL) was performed with oxygen free saline. BAL was centrifuged and separated into BAL fluid (BALF) and BAL cells (BALC) and analyzed for indication of lung injury. The edema by dry/wet weight ratio of the accessory lobe increased 11% in VX-treated animals. BAL cell number was increased in VX-treated animals compared to controls, independent of dosage. Trypan blue viability assay indicated an increase in BAL cell death in 70.4 μg/m^m3 and 90.4 μg/m^m3 VX-exposed animals. Differential cell counting of BALC indicated a decrease in macrophage/monocytes in VX-exposed animals. The total amount of BAL protein increased gradually with the exposed dose of VX and was highest in animals exposed to 90.4 μg/m^m3, indicating that this dose of VX caused lung injury that persisted at 24 h. In addition, histopathology results also suggest that inhalation exposure to VX induces acute lung injury.     

Lung Tumor Induction by Inhalation Exposure to Molybdenum Trioxide in Rats and Mice

Inhalation studies of molybdenum trioxide (MoO₃) were conductedbecause of its wide use in industry, human exposure, and lackof data on carcinogenicity. Groups of 50 male and 50 femaleF344/N rats and B6C3F1 mice were exposed to MoO₃ by inhalationat 0, 10, 30, or 100 mg/m₃, 6 h/day, 5 days/week, for 2 years.In both rats and mice, survival and mean body weights of exposedgroups of males and females were similar to those of their respectivecontrols. There were significant exposure-dependent increasesin blood molybdenum concentration in exposed rats and mice.There were no toxicological differences in bone density or curvaturebetween exposed animals and their respective controls. In rats,dose-dependent increases in incidence of hyaline degenerationin the nasal olfactory epithelium and squamous metaplasia ofthe epithelium lining the base of the epiglottis were observed.The incidence of alveolar/bronchiolar adenoma or carcinoma (combined)was marginally increased in males but not in females comparedwith controls. In mice, the incidences of squamous metaplasiaof the epithelium lining the base of the epiglottis, hyperplasiaof the laryngeal epithelium, and metaplasia of the alveolarepithelium were significantly increased in all exposed malesand females compared with controls. The incidence of alveolar/bronchiolaradenoma or carcinoma (combined) in exposed groups of males andfemales was significantly greater than that in the control groups.     

Lung Function Changes in Sprague-Dawley Rats After Prolonged Inhalation Exposure to Silver Nanoparticles

The antimicrobial activity of silver nanoparticles has resulted in their widespread use in many consumer products. However, despite the continuing increase in the population exposed to silver nanoparticles, the effects of prolonged exposure to silver nanoparticles have not been thoroughly determined. Accordingly, this study attempted to investigate the inflammatory responses and pulmonary function changes in rats during 90 days of inhalation exposure to silver nanoparticles. The rats were exposed to silver nanoparticles (18 nm diameter) at concentrations of 0.7 × 10⁶ particles/cm³ (low dose), 1.4 × 10⁶ particles /cm³ (middle dose), and 2.9 × 10⁶ particles /cm³ (high dose) for 6 h/day in an inhalation chamber for 90 days. The lung function was measured every week after the daily exposure, and the animals sacrificed after the 90-day exposure period. Cellular differential counts and inflammatory measurements, such as albumin, lactate dehydrogenase (LDH), and total protein, were also monitored in the acellular bronchoalveolar lavage (BAL) fluid of the rats exposed to the silver nanoparticles for 90 days. Among the lung function test measurements, the tidal volume and minute volume showed a statistically significant decrease during the 90 days of silver nanoparticle exposure. Although no statistically significant differences were found in the cellular differential counts, the inflammation measurements increased in the high-dose female rats. Meanwhile, histopathological examinations indicated dose-dependent increases in lesions related to silver nanoparticle exposure, such as infiltrate mixed cell and chronic alveolar inflammation, including thickened alveolar walls and small granulomatous lesions. Therefore, when taken together, the decreases in the tidal volume and minute volume and other inflammatory responses after prolonged exposure to silver nanoparticles would seem to indicate that nanosized particle inhalation exposure can induce lung function changes, along with inflammation, at much lower mass dose concentrations when compared to submicrometer particles.     

Chronic Toxicity/Oncogenicity of Dimethylformamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylformamide(DMF) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 400 ppm DMF for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanasiafor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks, 3 months, and 12 months.No compound-related effects on clinical observations or survivalwere observed. Body weights of rats exposed to 100 (males only)and 400 ppm were reduced. Conversely, body weights were increasedin 400 ppm mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 100 or 400 ppm. There were no compound-relatedeffects on the estrous cycle of rats or mice at any concentration.Compound-related morphological changes were observed only inthe liver. In rats, exposure to 100 and 400 ppm produced increasedrelative liver weights, centrilobular hepatocellular hypertrophy,lipofuscin/hemosiderin accumulation in Kupifer cells, and centrilobularsingle cell necrosis (400 ppm only). In mice, increased liverweights (100 ppm males, 400 ppm both sexes), centrilobular hepatocellularhypertrophy, accumulation of lipofuscin/hemosiderin in Kupffercells, and centrilobular single cell necrosis were observedin all exposure groups. These observations occurred in a dose-responsefashion and were minimal at 25 ppm. No increase in hepatic cellproliferation was seen in mice or female rats. Slightly higherproliferation was seen in male rats exposed to 400 ppm at 2weeks and 3 months but not at 12 months. Dimethylformamide wasnot oncogenic under these experimental conditions in eitherthe rat or mouse.     

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylacetamide(DMAC) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanizationfor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks and 3 and 12 months.No compound-related effects on survival were observed. Ratsexposed to 350 ppm had lower body weight and/or body weightgain. There were no compound-related effects on body weightor weight gain in mice at any concentration. There were no compound-relatedadverse effects on the incidence of clinical signs of toxicityin rats or mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 350 ppm. Serum cholesterol and glucose concentrationswere significantly higher in 100 and 350 ppm female rats. Compound-relatedmorphological changes were observed in the liver. In rats, exposureto 100 or 350 ppm produced increased absolute and/or relativeliver weights, hepatic focal cystic degeneration, hepatic peliosis,biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderinaccumulation in Kupffer cells. In mice, exposure to 100 or 350ppm produced increased absolute and relative liver weights (350ppm females only), accumulation of lipofuscin/hemosiderin inKupifer cells, and centrilobular single cell necrosis. Malerats exposed to 350 ppm also had significantly higher absoluteand relative kidney weights which correlated with the grossand microscopic changes resulting from a compound-related increasein severity of chronic progressive nephropathy. Female miceexposed to 350 ppm had an increased incidence of bilateral,diffuse retinal atrophy. No increase in hepatic cell proliferationwas seen in mice or rats at any exposure concentration. DMACwas not oncogenic under these experimental conditions in eitherthe rat or mouse. The NOAEL for male and female rats and miceis 25 ppm.     

Butyrylcholinesterase in Guinea Pig Lung Lavage: A Novel Biomarker to Assess Lung Injury Following Inhalation Exposure to Nerve Agent VX

Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 μ g/m³ VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 μ g/m³ and 90.4 μg/m³, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.     

Olfactory Mucosal Lesions in F344 Rats Following Inhalation Exposure to Pyridine at Threshold Limit Value Concentrations

Pyridine is a volatile solvent used as an intermediate in theproduction of insecticides, herbicides, pharmaceuticals, anddyes. Pyridine is also found in tobacco smoke. Because inhalationis a primary route of exposure to pyridine, we examined theeffect of inhaled pyridine on morphology at the portal of entry,the nose. Nasal tissues from F344/N rats exposed using a noseonlymode 6 hr/day for 4 days to either filtered air (controls) orone of two concentrations of pyridine vapor were examined histologically.The rats had been killed 18 hr after the last exposure. Thetwo pyridine concentrations were the current threshold limitvalue (TLV, 5 ppm) and a high concentration (444 ppm). Olfactoryepithelial lesions in rats exposed to both concentrations ofpyridine included vacuolar degeneration of sustentacular cells;focal, marked attenuation of the epithelium; loss of vacuolardegeneration of sustentacular cells; focal, marked attenuationof the epithelium; loss of neurons; and the presence of intraepithelialluminal structures. The lesions were only slightly more severein the rats exposed to 444 ppm compared to those rats exposedto 5 ppm pyridine. The results show that inhalation of pyridineat the current TLV concentration of 5 or 444 ppm causes lesionsin the olfactory epithelium of rats.     

DNA Methylation,Cell Proliferation,and Histopathology in Rats Following Repeated Inhalation Exposure to Dimethyl Sulfate

Dimethyl sulfate (DMS) is an alkylating agent that is carcinogenic to the respiratory tract of rodents. DNA adducts, cell proliferation, and histopathology were assessed in rats to better understand the molecular dosimetry and tissue dynamics associated with repeated inhalation exposure to DMS. For DNA methylation, rats were exposed to DMS vapor 6 h/day for up to 10 days to 0.0, 0.1, 0.7 and 1.5 ppm. N⁷-Methylguanine and N³-methyladenine were detected in neutral thermal hydrolysates of DNA isolated from respiratory tract tissues by high-performance liquid chromatography (HPLC) using fluorescence and ultraviolet (UV) detection. DNA methylation was greatest in DNA isolated from nasal respiratory mucosa, less in olfactory, and little was found in lung. N⁷-Methylguanine levels in respiratory mucosa approached steady-state levels by day 5, and N⁷-methylguanine persistence following exposure for 5 consecutive days was also determined. Loss of N⁷-methylguanine from respiratory and olfactory mucosa appeared to follow first-order kinetics. N³-Methyladenine levels were at or below detection limits in all samples. The effect of DMS on histopathology and cell proliferation in the nasal epithelium was also investigated. Rats were exposed nose-only for 2 wk to DMS vapor at concentrations of 0, 0.1, 0.7, or 1.5 ppm. Inhalation exposure to DMS induced degenerative and inflammatory changes in nasal epithelium at ≥0.7 ppm. Cell proliferation evaluations showed a trend towards an increased response at 1.5 ppm. These experiments demonstrate that DMS can induce cytotoxic and proliferative effects and is a potent methylating agent of the nasal mucosa in vivo. These experiments will provide data for the development of dosimetry models useful for risk extrapolation.     

Improved Pharmacokinetic Characteristics of Ursolic Acid in Rats Following Intratracheal Instillation and Nose-Only Inhalation Exposure

Ursolic acid (UA) is a common pentacyclic triterpene phytochemical with various pharmacological activities. However, UA is classified as a class IV drug in BCS system and its development as an oral drug is limited. Pulmonary delivery is an effective way to improve the bioavailability of drugs with low absorption. In this study, the differences in pharmacokinetic behaviors of UA after pulmonary and oral administration was explored in rats. Compared with oral administration, the plasma concentration of UA increased rapidly after pulmonary administration, and the bioavailability increased about 80 times. UA instantly accumulated in the lungs after pulmonary administration, and the pulmonary AUC_0-t/dose increased by 114 times compared to oral dosing. Incubation experiments showed that the metabolism of UA in rat lung microsomes was significantly reduced compared with that in liver microsomes, in which the clearance rate of phase I and phase II metabolism was reduced by 14.7 times and 1.4 times respectively. These results indicated that pulmonary administration could improve the bioavailability of UA and reduce its metabolism. This study not only provides a preferable route of administration for the application of UA but also offers new insights for the development of phytochemical drug candidates with poor pharmacokinetic properties.     

Toxicokinetics of Propylene Glycol Mono-t-Butyl Ether Following Intravenous or Inhalation Exposure in Rats and Mice

Propylene glycol mono-t-butyl ether (PGMBE) is a widely used solvent in industry and in consumer products, posing a potential for human exposure via inhalation or dermal routes. Toxicokinetic studies were conducted on F344/N rats and B6C3F1 mice of both sexes to evaluate single or repeated dose, species, and/or sex differences in PGMBE elimination kinetics following intravenous or inhalation exposure. In the first study, rats and mice received a single intravenous dose of 15 or 200 mg PGMBE/kg and serial blood samples were collected and analyzed for PGMBE. In the second study, rats and mice received a single 6-h whole-body inhalation exposure to 75, 300, or 1200 ppm PGMBE and serial blood samples were collected and analyzed for PGMBE. In the third study, rats and mice received whole-body inhalation exposures to 75, 300, or 1200 ppm PGMBE for 6 h/day, 5 days/wk for 14 (rats) or 16 (mice) wk. Serial blood samples were analyzed for PGMBE after 2, 6, 14 (rats), and 16 (mice) wk on study. Urine samples were also collected for 16 h postexposure and analyzed for creatinine and PGMBE sulfate and PGMBE glucuronide conjugates. These studies revealed that: (1) PGMBE was eliminated from blood following concentration-dependent nonlinear kinetics in both species; (2) saturable Michaelis–Menten kinetics were clearly exhibited following a single inhalation exposure at 1200 ppm, but were less obvious following repeated exposures; (3) mice were more efficient in eliminating PGMBE from blood at lower exposure concentrations (i.e., ≤300 ppm), but at exposure concentrations potentially exceeding their elimination capacity, mice had a greater concentration-dependent decrease in PGMBE elimination than rats; (4) there were minimal but consistent sex differences in PGMBE elimination profiles for rats, with females having higher blood concentrations at all exposure concentrations and sampling times; and (5) sex differences in PGMBE elimination were in part associated with differences in urinary excretion of PGMBE metabolites.     

Methylene Chloride: A 2-Year Inhalation Toxicity and Oncogenicity Study in Rats

Methylene Chloride: A 2-Year Inhalation Toxicity and OncogenicityStudy in Rats. Nit-schke, K. D. Burek, J. D., Bell, T. J., Kociba,R. J., Rampy, L. W. and McKenna, M. J. (1988). Fundam. Appl.Toxicol. 11, 48-59. Male and female Sprague-Dawley rats wereexposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day,5 days/week for 2 years. Blood carboxyhemoglobin levels wereelevated in a dose-dependent (less than linear) manner in ratsexposed to 50–500 ppm methylene chloride Histopathologiclesions related to methylene chloride exposure were confinedto the liver and mammary tissue of rats. An increased incidenceof hepatocellular vacuolization was observed in male and femalerats exposed to 500 ppm methylene chloride. Female rats exposedto 500 ppm methylene chloride also had an increased incidenceof multinucleated hepatocytes and number of spontaneous benignmammary tumors/ tumor-bearing rat (adenomas, fibromas, and fibroadenomaswith no progression toward malignancy); the incidence of benignmammary tumors in female rats exposed to 50 or 200 ppm methylenechloride was comparable to historical control values. No increasein the number of any malignant tumor type was observed in ratsexposed to concentrations as high as 500 ppm methylene chloride.Additional groups of female rats were exposed to 500 ppm methylenechloride for the first 12 months or the last 12 months of the24-month study. The response observed in female rats exposedto 500 ppm for the first 12 months was the same as that observedin female rats exposed to 500 ppm for 2 years. Conversely, theresponse observed in female rats exposed to 500 ppm during thelast 12 months of the study was similar to that observed incontrol animals. Based upon the results of this study, the no-adverse-effectlevel for chronic inhalation exposure of Sprague-Dawley ratswas judged to be 200 ppm methylene chloride.     

The Influence of Sarin on Various Physiological Functions in Rats Following Single or Repeated Low-Level Inhalation Exposure

Long-term effects of low doses of highly toxic organophosphorus agent sarin on various hematological and biochemical markers and physiological functions were studied in rats exposed to sarin by inhalation. The results indicate that low-level sarin-exposed rats show long-term increase in studied markers of stress and decrease in synthesis of DNA de novo without the disturbance of the functions of cholinergic nervous system. Moreover, sarin at low doses is able to induce some neurotoxic effects including an increase in the excitability of central nervous system in rats at 3 mo following inhalation exposure. Relatively long-term spatial discrimination impairments in rats exposed to low-level sarin was demonstrated too. Therefore, nerve agents such as sarin seem to be harmful not only at high, clinically symptomatic doses but also at low doses without acute clinical manifestation of overtimulation of cholinergic nervous system because of long-term manifestation of alteration of neurophysiological and neurobehavioral functions in sarin-exposed rats.     

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.     

Twenty-Eight-Day Repeated-Dose Inhalation Exposure of Rats to Diethylene Glycol Monoethyl Ether

This study was carried out to provide information on the effectsof inhalation of diethylene glycol monoethyl ether, a substanceused in industry which may be accidentally inhaled by man. Sprague-DawleyCD rats were exposed by inhalation to a test atmosphere containingdiethylene glycol monoethyl ether in a nose-only exposure systemfor 6 hr a day, 5 days a week for 28 days. Mean exposure levelswere 0.09, 0.27, and 1.1 mg/liter. At the two lowest exposurelevels the test substance was present entirely as vapor, butat the highest exposure level the test atmosphere was approximatelyequally divided by mass into respirable droplets (aerosol) andvapor. A comprehensive battery of toxicological evaluationsincluding food consumption, body weight, clinical signs, hematology,and biochemistry revealed no evidence of a systemic effect ofexposure. Histopathological examination showed changes indicativeof mild nonspecific irritation in the upper respiratory tractof rats exposed at the two highest exposure levels. These changesconsisted of foci of necrosis in the ventral cartilage of thelarynx of rats exposed at 0.27 or 1.1 mg/liter and an increasein eosinophilic inclusions in the olfactory epithelium of thenasal mucosa of rats exposed at 1.1 mg/liter. The no observedadverse effect level for systemic effects was 1.1 mg/liter andthe no observed adverse effect level for signs indicative ofmild nonspecific irritation of the upper respiratory tract was0.09 mg/liter.     

Inhalation Toxicology of Decamethylcyclopentasiloxane (D5) Following a 3-Month Nose-Only Exposure in Fischer 344 Rats

D₅ is a low-molecular-weight cyclic siloxane used for industrialand consumer product applications. The objective of the presentstudy was to evaluate the subchronic toxicity of D₅ followinga 3-month nose-only inhalation exposure. In addition, animalsfrom both sexes of the control and high dose groups were alloweda 4-week recovery period to observe reversibility, persistence,or delayed occurrence of any potential adverse effects. Maleand female Fischer 344 rats were exposed for 6 h/day, 5 days/weekfor 3 months to target concentrations of 0 (30/sex/group), 26(20/sex/group), 46 (20/sex/group), 86 (20/sex/group), and 224(30/sex/ group) ppm D₅. Recovery groups (0 and 224 ppm) comprised10 rats/sex/group. Body weights and food consumption were monitoredat least twice weekly over the course of exposures. Approximately16 h preceding euthanasia, animals were transferred into metabolismcaging for urine collection and were fasted. Rats were anesthetizedwith pentobarbital and euthanized by exsanguination. Blood wascollected for hematological and clinical biochemical analyses.Selected organ weights were measured and a complete set of tissueswas taken for histopathological examination. There were severalminor changes observed in clinical biochemistry parameters;the most notable was an increase in gamma glutamyl transferase(     

Studies on the Prenatal Toxicity of 3-Methyl-1-butanol and 2-Methyl-1-propanol in Rats and Rabbits Following Inhalation Exposure

3-Methyl-1-butanol (MEB) and 2-methyl-1-propanol (MEP) weretested for their prenatal inhalation toxicity in pregnant Wistarrats or Himalayan rabbits. Twenty-five female rats and 15 femalerabbits per group were exposed to MEB and MEP vapors at concentrationsof 10, 2.5, or 0.5 mg/liter, 6 hr/day. The rats were exposedon Days 6–15 postcoitum (pc) and the rabbits were exposedon Days 7–19 postinsemination (pi). Control groups wereexposed to clean air. The body weights of the animals of eitherspecies were determined several times throughout the studies.All rats and all rabbits were killed on Day 20 pc and Day 29pi, respectively. The fetuses were removed from the uterus andexamined for compound-related effects. The high concentrationof 10 mg/liter caused a slight retardation of body weight gainin the dams of either species exposed to MEB and in the damsof rabbits exposed to MEP during the first days of the exposureperiod. Eye irritation was observed only in the MEB-treatedrabbits during the period of exposure to 10 mg/liter. The fetusesof either species exhibited no signs of embryo-/fetotoxicityor teratogenic effects caused by MEP or MEB. Under the experimentalconditions, 2.5 mg/liter was found to be a no-observable-adverse-effectlevel (NOAEL) for the dams of either species exposed to MEBand for the does exposed to MEP, whereas 10 mg/liter MEP wasthe NOAEL for the maternal rats. For both substances 10 mg/literwas defined as the NOAEL for the conceptuses of either species.     

Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber: I. Quantitation of Lung and Pleural Fiber Burdens

The pleura is an important target tissue of fiber-induced disease,although it is not known whether fibers must be in direct contactwith pleural cells to exert pathologic effects. In the presentstudy, we determined the kinetics of fiber movement into pleuraltissues of rats following inhalation of RCF-1, a ceramic fiberpreviously shown to induce neoplasms in the lung and pleuraof rats. Male Fischer 344 rats were exposed by nose-only inhalationto RCF-1 at 89 mg/m³ (2645 WHO fibers/cc), 6 hr/day for 5 consecutivedays. On Days 5 and 32, thoracic tissues were analyzed to determinepulmonary and pleural fiber burdens. Mean fiber counts were22x10⁶/lung (25x10³/pleura) at Day 5 and 18x10⁶ (16x10/pleura)at Day 32. Similar geometric mean lengths (GML) and diameters(GMD) of pulmonary fiber burdens were observed at both timepoints. Values were 5 µm for GML (geometric standard deviationGSD 2.3) and 0.3 µm for GMD (GSD 1.9), with correlationsbetween length and diameter () of 0.2–0.3. Size distributionsof pleural fiber burdens at both time points were approximately1.5 µm GML. (GSD 2.0) and 0.09 µm GMD (GSD 1.5; 0.2–0.5). Few fibers longer than 5 µm were observedat either time point. These findings demonstrate that fiberscan rapidly translocate to pleural tissues. However, only short,thin (<5 µm in length) fibers could be detected overthe 32-day time course of the experiment.