The Effects of Inhalation Exposure to Sulfuryl Fluoride on Fetal Development in Rats and Rabbits

Sulfuryl fluoride is a fumigant insecticide used for soils andpermanent structures. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 25, 75, or 225 ppm of sulfurylfluoride vapor via inhalation for 6 hr/day on Days 6–15and 6–18 of gestation, respectively. Among rats, maternalwater consumption was increased in the 225 ppm exposure group,but there were no indications of embryotoxicity, fetotoxicity,or tera-togenicity in any of the exposed groups. Among rabbits,maternal weight loss during the exposure period (Days 6–18)was observed in the 225 ppm group. Decreased fetal body weights,considered secondary to maternal weight loss, were also observedat 225 ppm. However, no evidence of embryotoxicity or teratogenicitywas observed among rabbits in any exposure group. Thus, inhalationexposure to sulfuryl fluoride was not teratogenic in eitherrats or rabbits exposed to levels of up to 225 ppm, and fetotoxiceffects (reduced body weights) were observed among fetal rabbitsonly at an exposure level that produced maternal weight loss.     

Mercapturic Acid Excretion by Rats following Inhalation Exposure to m1,3-Dichloropropene

Mercapturic Acid Excretion by Rats following Acute InhalationExposure to 1,3-Dichloro-propcne. Fisher, G. D., and Kjlgore,W. W. (1988). Fundam Appl. Toxicol. 11, 300–307. Ratswere exposed to 1,3-dichloropropene (DCP), a commonly used agriculturalnematicide, by inhalation to assess the relationship betweenDCP concentration and the urinary excretion of the mercapturicacid of cis-DCP (3C-NAC). The nose-only exposure system thatwas used for simultaneously exposing up to four rodents is described.This apparatus provided for generation and monitoring of relativehumidity and test vapor concentration. Animals were exposedfor 1 hr to concentrations of up to 789 ppm DCP. Urine was collectedfor 24 hr after exposure. The quantity of 3C-NAC contained inthe urine collections exhibited an exposure concentration-dependentincrease from 0 to 284 ppm DCP. However, the amount of 3C-NACwas no greater for animals exposed to 398 or 789 ppm DCP thanfor animals exposed to 284 ppm DCP. C 1988 Society of Toxicology     

1,3-Dichloropropene: Two-Generation Inhalation Reproduction Study in Fischer 344 Rats

1,3-Dichloropropene: Two-Generation Inhalation ReproductionStudy in Fischer 344 Rats. BRESLIN, W. J., KIRK, H. D., STREETER,C. M., QUAST, J. F.,AND SZABO, J. R. (1989). Fundam. Appl Toxicol.12, 129–143. This study evaluated the effects of inhaledtechnical-grade 1,3-dichloropropene (DCPT) on reproduction andneonatal growth and survival. Groups of 30 male and 30 femaleFischer 344 rats, approximately 6 weeks of age, were exposedvia inhalation to 0, 10, 30 or 90 ppm DCPT for 6 hr/day, 5 days/week,for two generations. The parental f₀ and f₁ generations wereeach bred twice. Reproductive and neonatal parameters evaluatedincluded indices of fertility and pup survival, gestation length,litter size, pup body weight, and pup sex ratio. Gross and histologicexaminations were conducted on all f₀ and f₁ adults. In addition,randomly selected f_1b and f_2b weanlings were given gross examinations.Parental effects were limited to rats exposed to 90 ppm DCPTand included decreased body weights and histopathologic effectson the nasal mucosa of adult male and female rats. The histopathologiceffects consisted of slight, focal hyperplasia of the respiratoryepitheium and/or focal degenerative changes in the olfactoryepithelium. No adverse effects on reproductive parameters orneonatal growth or survival were observed in the f_1a, f_1b, f_2a,or f_2b litters even at an exposure concentration which producedeffects in adult animals. Based on these results, it is concludedthat inhalation exposure of rats up to 90 ppm DCPT for two successivegenerations did not adversely affect the reproductive and neonatalparameters evaluated.     

Effects of Subchronic Inhalation of D-D (1,3-Dichloropropene/1,2-Dichloropropane) on Reproduction in Male and Female Rats

Effects of Subchronic Inhalation of D-D (1,3-Dichloropropene/l,2-Dichloropropane) on Reproduction in Male and Female Rats.LINNETT, S. L., CLARK, D. G., BLAIR, D., AND CASSIDY, S. L.(1988). Fundam. Appl. Toxicol. 10, 214-223. The effects of inhaledD-D (1,3-dichloropro-pene/1,2-dichloropropane) on reproductionwere studied in rats of both sexes. The rats inhaled nominalconcentrations of 0, 10, 30, or 90 ppm (v/v) D-D for 6 hr/day,5 days/week for 10 weeks. Treated males of proven fertilitywere paired with untreated virgin females at intervals duringand after exposure. Treated females were paired with untreatedmales immediately after the 10-week exposure period. Variousaspects of reproductive performance and general toxicity wereassessed. Exposure to D-D produced no adverse effects on thelibido, fertility, or morphology of the reproductive tractsof rats of either sex; no treatment-related dominant lethaleffect was observed in male rats. Slight reductions in bodyweight gains and slight increases in liver and kidney weightswere observed in 90 ppm rats of both sexes.     

Bioavailability and Pharmacokinetics of Microencapsulated 1,3-Dichloropropene in Rats

The potential oral toxicity of 1,3-dichloropropene (1,3-D) hasbeen evaluated in a number of dietary toxicity studies. Therelatively high vapor pressure of 1,3-D, its short half-lifein drinking water, and its reactivity with constituents of feednecessitated the use of a microencapsulated formulation (starch-sucroseshell) of 1,3-D in these studies. The bioavailability of ingestedmicroencapsulated 1,3-D was determined by characterizing andcomparing the kinetics of 1,3-D in the blood of female F344rats coadminis-tered microencapsulated 1,3-D and neat ¹³C-1,3-D(25 mg/kg each) via gavage. Blood concentrations of total orcis- and trans-is-isomers of 1,3-D in treated rats were determinedusing gas chromatography-mass spectroscopy (GC-MS) or in situmembrane extraction MS. Urine was also collected and analyzedby GC-MS for the presence of the mercapturate excretion productof 1,3-D [N-acetyl-S-(3-chloropropenyl-2)L-cysteine; 1,3-DMA].Blood levels of 1,3-D and ¹³C-1,3-D displayed similar kinetics,peaking within 10 min of dosing followed by a rapid biphasicelimination. Higher peak blood levels and greater blood curveareas (AUC) were attained for trans- than cis-l,3-D and ¹³C-1,3-Dand greater amounts of cis- than trans-l,3-DMA and ¹³C-1,3-DMAwere excreted in the urine consistent with the known rapid anddisproportionate glutathione conjugation of the cis-isomer inthe gastric mucosa. Slightly higher ^cis-l,3-D than cis-¹³C-l,3-Dblood levels and AUCs were also consistently noted while thereverse was true for urinary excretion of cis-¹³C-13-DMA andcis-l,3-DMA suggesting that 1,3-D derived from microencapsulatedtest material may be absorbed and/or metabolized in the stomachmucosa at a slightly slower rate than that from neat material.The latter, however, would be of no consequence during the administrationof 1,3-D to animals via their diets as competing test materialswould not be present and 1,3-D blood kinetics were unaffected.Overall, the results of this study demonstrate the ready bioavailabilityof microencapsulated 1,3-D and rapid elimination of 1,3-D fromthe blood of rats.     

Subchronic Toxicity of Ingested 1,3-Dichloropropene in Rats and Mice

Male and female Fischer 344 rats and B6C3F1 mice (10/sex/dosegroup) were given 0, 5, 15, 50, or 100 mg/kg/day (rats) or 0,15, 50, 100, or 175 (mice) mg/kg/day racemic 1,3-dichloropropene(1,3-D), respectively, via their diets for 13 weeks. Satellitegroups of rats (recovery = 10 rats/sex/group) ingesting 0 or100 mg/kg/day 1,3-D were provided control feed for an additional4 weeks to examine recovery. The test material was stabilizedin the feed by microencapsulation in a starch/sucrose matrix(80/20). The body weights of male and female rats Ingesting>5 and >15 mg/kg/day, respectively, and of all treatmentgroups of mice were decreased relative to controls. The terminalbody weights of high dose group rats and mice were decreasedapproximately 13–16%. A number of changes in serum biochemicalparameters and decreases in organ weights accompanied the depressedbody weights of these animals. Histologically, the only treatment-relatedchange observed was a slight degree of basal cell hyperplasiaand hyperkeratosis in the nonglandular portion of the stomachsof a majority of male and female rats ingesting >15 mg/kg/day.After the 4-week recovery period, most treatment-related changeswere noted to be reversible in nature. No treatment-relatedhistopathological changes were observed in the tissues of treatedmice. Based upon relatively slight depressions in body weightsat the lowest dosages tested, the no-observed-adverse-effectlevels for male rats and both sexes of mice were determinedto be 5 mg/kg/day and 15 mg/kg/day, respectively. A no-observed-effectlevel of 5 mg/kg/day was established for female rats.     

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widelyused as an industrial solvent) vapors, 6 hr/day, 7 days/week(6–19 days of gestation (DG) for rats; 6–17 DG formice). Body weights of pregnant rats in the 5000 ppm group werereduced at euthanization. There were no effects on the percentageof live rat fetuses/litter or on the fetal sex ratio. Fetalbody weight was significantly reduced for the 5000 ppm group,but the incidence of abnormalities was not increased. Mice inthe 1800 and 5000 ppm groups were sedated during exposure; approximately27% of the mice in the 5000 ppm group died. Mean body and uterineweights of mice were reduced for the 1800 and 5000 ppm groupsat euthanization (18 DG), but adjusted maternal weight gainwas not affected at 1800 ppm. There was a reduction in the percentageof live fetuses/litter for the mice in 1800 and 5000 ppm groups(95% resorptions in the 5000 ppm group). Fetal weight and sexratio in mice were not affected. An increase in the incidenceof reduced sternebral ossifications was correlated to THF concentration,although differences between groups were not statistically significant.There were no increases in the incidences of other malformationsor variations. These results suggest that THF may be embryotoxicin mice, but if the conceptus survives, development as assessedby this experimental design continues in a normal fashion. Theno-observable-adverse-effect level (NOAEL) for maternal toxicitywas 1800 ppm in both rats and mice. The NOAEL for developmentaltoxicity was 1800 ppm in rats and 600 ppm in mice.     

Subchronic Toxicity of Inhaled Technical Grade 1,3-Dichloropropene in Rats and Mice

Subchronic Toxicity of Inhaled Technical Grade 1,3-Dichloropropenein Rats and Mice. Stott, W. T., Young, J. T., Calhoun, L. L.,and Battjes, J. E., (1988). Fundam. Appl. Toxicol. 11,207–220.In order to provide a comprehensive subchronic inhalation toxicitystudy of the soil fumigant, technical grade 1,3-dichloropropene(DCPT), male and female Fischer 344 rats and B6C3F1 mice wereexposed to 0, 10, 30,90, or 150 ppm DCPT vapors 6 hr/day, 5days/ week for 13 weeks. The primary target tissues of inhaledDCPT were identified as the nasal mucosa of both sexes of ratsand mice, and the urinary bladder of female mice. In addition,depressed growth rates of all animals exposed to 90 or 150 ppmDCPT (up to 20% in rats and 12% in mice) resulted in a varietyof alterations in hematologjc and clinical chemistry parameters,and changes in organ weights relative to controls. Nasal mucosaleffects consisted of a dose-related slight degenerative effectof nasal olfactory epithelium or a mild hyperplasia of the respiratoryepithelium or both in all animals exposed to 90 or 150 ppm and2 of 10 male rats exposed to 30 ppm DCPT. Some focal areas ofrespiratory metaplasia were also noted in high exposure groupmice. Urinary bladder effects consisted of a diffuse, moderatehyperplasia of the transitional epithelium in female mice exposedto 90 or 150 ppm DCPT. No treatment-related effects were observedin rats or mice exposed to 10 ppm DCPT vapors.     

Inhalation Toxicity of Sulfuryl Fluoride in Rats and Rabbits

Inhalation Toxicity of Sulfuryl fluoride in Rats and Rabbits.EISENBRANDT, D. L., AND NITSCHKE, K. D. (1989). Fundam Appl.Toxicol 12, 540–557. The inhalation toxicity of the structuralfumigant sulfuryl fluoride (SO₂F₂) was evaluated in rats andrabbits. Exposures for a preliminary 2-week study were 6 hr/day,5 days/week, to 0, 100, 300, or 600 ppm SO₂F₂ Nine often ratsat 600 ppm died or were moribund between the second and sixthexposures. Extensive kidney lesions were present in all ratsexposed to 600 ppm, whereas only minimal renal changes werenoted in rats at 300 ppm. Upper and lower respiratory tissueswere inflamed in the single rat that survived the 2-week exposureto 600 ppm. Rabbits exposed to 600 ppm SO₂F₂ were hyperactiveand one animal had a convulsion. Exposure to 300 or 600 ppmfor 2 weeks resulted in vacuolation and/or malacia in the cerebrumof all rabbits and most of these rabbits also had moderate inflammationof nasal tissues; a few rabbits at 600 ppm had inflammationof the trachea or bronchi. A subsequent 13-week study evaluatedrats and rabbits exposed to 0, 30, 100, or 300 ppm SO₂F₂ (337ppm TWA for rabbits). Rabbits initially were exposed to a highconcentration of 600 ppm; however, convulsions were noted intwo animals after nine exposures and the concentration subsequentlywas reduced to 300 ppm. Vacuolation and/or malacia were observedin the cerebrum of all rabbits at the highest concentration;one rabbit exposed to 100 ppm also had cerebral vacuolation.Rabbits at the highest concentration, as well as one rabbitexposed to 100 ppm, had inflammation of the nasal tissues. Ratsexposed to 300 ppm SO₂F₂ for 13 weeks had mottled incisor teeth,minimal renal effects, pulmonary histiocytosis, inflamma tionof nasal tissues, and cerebral vacuolation. Also, rats exposedto 100 ppm SO₂F₂ for 13 weeks had mottled teeth. fluoride toxicitywas suggested by mottled teeth in rats as well as elevationof serum fluoride levels in rats and rabbits exposed to SO₂F₂for 13 weeks. Although repeated exposure of rats and rabbitsto 100–600 ppm SO₂F₂ resulted in toxicity ofthe kidneys(rats only), brain, and respiratory system, no effects weredetected in animals exposed to 30 ppm for 13 weeks.     

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.     

The Chronic Toxicity and Oncogenicity of Inhaled Technical-Grade 1,3-Dichloropropene in Rats and Mice

The Chronic Toxicity and Oncogenicity of Inhaled Technical-Grade1,3-Dichloropropene in Rats and Mice. LOMAX, L, G., STOTT, W.T., JOHNSON, K. A., CALHOUN, L. L., YANO, B. L., AND QUAST,J. F. (1989). Fundam. Appl. Toxicol. 12, 418–431. Maleand female Fischer 344 rats and B6C3F1 mice were exposed byinhalation to target concentrations of 0, 5, 20, or 60 ppm (0,22.7, 90.8, or 272 mg/m³) technical-grade 1,3-dichloropropene(DCPT) 6 hr/day, 5 days/week, for upto 2 years. Ancillary groupsof rats and mice were exposed for 6- and 12- month periods.Significant treatment-related nonneoplastic changes followingexposure for 2 years were morphological alterations in the nasaltissues of rats exposed to 60 ppm and mice exposed to 20 or60 ppm DCPT. In addition, mice exposed to 20 or 60 ppm had hyperplasiaof the transitional epithelium lining the urinary bladder. Survivalof male and female rats and mice exposed to DCPT was similarto that of the corresponding controls. No statistically increasedtumor incidence was observed in treated rats. The only neoplasticresponse observed in mice was an increased incidence of benignlung tumors (bronchioloalveolar adenomas) in male mice exposedto 60 ppm DCPT (22/50 versus 9/50 in controls).     

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.     

Effects of Lead Exposure on Skeletal Development in Rats

The effects of lead on growth in female rats and on growth andskeletal development in their offspring were investigated. Noalteration in growth rate, compared to the growth rate in pair-fedcontrols, was observed in 48 weanling females continuously exposedto 250 or 1000 ppm lead in drinking water and fed a repletediet. After 49 days of exposure, all rats (24 pair-fed controls,12 exposed to 250 ppm lead, and 12 exposed to 1000 ppm lead)were mated with control males. At parturition, six lactatingdams each from the 250 and 1000 ppm lead groups were removedfrom lead exposure and given control drinking water, and sixlactating dams each from the control group were given either250 or 1000 ppm lead in drinking water. Exposure conditionsfor the remaining dams in the control, 250, and 1000 ppm groupswere not changed. Maternal blood lead in the continuously lead-exposedgroups was higher at the end of lactation than prior to mating.Lead exposure prior to parturition caused greater maternal tibiallead accumulation than lead exposure after parturition. In contrast,lead exposure prior to parturition had a lesser impact on offspringtibial lead accumulation than lead exposure after parturition.Decreases in tibial calcium and phosphorus were observed indams exposed continuously to 250 or 1000 ppm lead; however,there was no apparent effect of lead on maternal growth-platemorphology or on growth-plate width. Offspring body weight wasdepressed relative to controls during suckling (Day 11) andafter weaning (Day 24) in high-dose and continuously lead-exposedgroups. Continuous lead exposure caused a greater decrease inoffspring body weight than lead exposure only prior to or afterparturition. Decreased tail length growth suggested possibleeffects of lead on tail vertebral bone growth. While tibialcalcium and phosphorus levels were not changed in the weanlings,increased weanling growth-plate width, with disruption of chondrocyteorganization, and wider metaphyseal trabeculae were observed.Although the mechanisms of these effects are not known, theresults suggest that local lead-related effects on growth-platechondrogenesis and metaphyseal mineralization may be involved.     

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.     

Effects of Six Months’White Spirit Inhalation Exposure in Adult and Old Rats

Abstract: In two separate experiments in rats the irreversible effects of six months'exposure to white spirit (0, 400 p.p.m., and 800 p,p.m.) were studied. In one experiment the exposure started at the age of three months, in the other the rats were 15 months at the beginning of the exposure. After an exposure-free period of several months neurobehavioural, pathological, and neurochemical examinations were performed. A marked difference in motor activity between young and aged animals was found. A slight effect on kidney function was seen at 800 p.p.m. No macroscopic or histopathological changes related to dosing were found. The concentrations of noradrenaline, dopamine, and 5-hydroxytryptamine in various brain regions and in whole brain were irreversibly changed. In conclusion, the study revealed different changes within the CNS, but failed to demonstrate neurobehavioural white spirit-induced neurotoxicity.     

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.     

Subchronic Inhalation Toxicity of Ethylbenzene in Mice, Rats, and Rabbits

Mice, rats, and rabbits (five/sex/group) were exposed by inhalationto ethylbenzene (EB) vapors for 6 hr/day, 5 days/week for 4weeks (20 exposures). Rats and mice received 0, 99, 382, or782 ppm EB while rabbits received 0, 382, 782, or 1610 ppm.No changes were evident in mortality patterns, clinical chemistries,urinalyses, or treatment-related gross/microscopic (includingophthalmologic) lesions. Rats exhibited sporadic lacrimationand salivation, as well as significantly increased liver weightsat 382 and 782 ppm, and small increases in leukocyte countsat 782 ppm. Males at this exposure level also showed marginalelevations in platelet counts. In mice, females showed statisticallyincreased absolute and relative liver weights at 382 and 782ppm, while males had statistically increased relative liver-to-brainweight ratios only at 782 ppm. Female rabbits at the high exposurelevel of 1610 ppm gained weight more slowly than controls (notstatistically significant); males showed a similar transientdownward trend after 1 week, but showed no differences fromcontrols at study's end. A no observed adverse effect level(NOAEL) of 382 ppm appears appropriate for rats and mice witha lowest observed adverse effect level (LOAEL) of 782 ppm. ANOAEL of 782 ppm and LOAEL of 1610 ppm are appropriate for rabbits.     

A Developmental Neurotoxicity Evaluation of the Effects of Prenatal Exposure to Fluoxetine in Rats

Fluoxetine is a widely used serotonin reuptake inhibitor effectivein the treatment of depression. This experiment assessed thepotential developmental neurotoxicity of fluoxetine. Sprague-DawleyCD rats were treated once per day on Days 7–20 of gestationwith 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolvedin distilled water. One control group received water by gavage;animals in this group were provided food and water ad libitum.The second control group (PF) also received water by gavage;animals in this group had their food and water restricted bypair-feeding and watering them to the 12 mg/kg fluoxetine group.Litters were culled to 12 after birth and offspring (male/femalepairs) were tested neurobehaviorally at three developmentalstages (preweaning, juvenile, and adult). At each stage, twopairs per litter received tests of locomotor activity, acousticstartle, and startle after administration of one of two pharmacologicalchallenges (one pair each receiving fluoxetine or apomorphine).Two pairs were also tested for spontaneous alternation, passiveavoidance, and complex learning in a water maze. At the highestdose, fluoxetine caused maternal weight loss during pregnancy,reduced litter sizes at birth, and increased neonatal mortality.No effects on long-term growth or survival were seen. Prenatalfluoxetine exposure produced no significant effects on locomotoractivity, spontaneous alternation, passive avoidance, or watermaze performance. A few scattered interactions involving treatmentgroup were obtained on startle, but no pattern of treatment-relatedchanges was evident. Regional wet and dry brain weights takenat each stage were not affected by prenatal fluoxetine exposure.The data suggest that fluoxetine is not developmentally neurotoxicin the rat.     

Four Weeks Inhalation Exposure to n-Heptane Causes Loss of Auditory Sensitivity in Rats

Abstract: The effects of exposure to 800 or 4000 p.p.m. of n-heptane, CAS No. [142-82-5]) 6 hr per day during a period of 28 days, on the function of the auditory system were examined by measurements of auditory brain stem response (ABR) in Long Evans rats. The ABR was measured simultaneously with both needle electrodes and implanted electrodes. The wave forms recorded with the two types of electrodes were similar, but the amplitudes were largest on the recordings with implanted electrodes. The overall ratio between the amplitudes obtained with implanted electrodes and with needle electrodes was 1.4 for peak la and 2.5 for peak IV of the ABR. The exposure to rc-heptane (4000 p.p.m.) reduced the amplitudes of components la and IV of the ABR. The reduction was most consistent for component IV and most pronounced at higher frequencies and intensities. The reduction in ABR corresponds to an increase in the auditory threshold of approximately 10 dB at all frequencies. Neither the latencies nor the interpeak latencies of components la and IV were changed. No significant changes in ABR were observed in the group exposed to 800 p.p.m. The mechanism behind the ototoxicity of organic solvents is discussed.     

Immunologic Tolerance in Rats during 13 Weeks of Inhalation Exposure to Trimellitic Anhydride

Immunologic Tolerance in Rats during 13 Weeks of InhalationExposure to Trimellitic Anhydride. LEACH, C. L., HATOUM, N.S., ZEISS, C. R., AND GARVIN, P. J. (1989). Fundam. Appl. Toxicol.12, 519–529. Trimellitic anhydride (TMA) causes severalimmunologically based pulmonary syndromes in humans. We developeda rat model representative of some of those syndromes wherebyrats exposed for 2 weeks to TMA by inhalation developed hemorrhagiclung foci and pneumonitis accompanied by the appearance of TMA-specificserum antibody. The purpose of the study reported here was toexamine the long-term, low-dose effects of TMA inhalation. Ratswere exposed to target concentrations of 0, 2, 15, or 50 µg/m³TMA 6 hr/day, 5 days/week for 13 weeks. The study included aninterim 6.5-week termination and two recovery periods of 3 and38 weeks, each with and without a final TMA inhalation challenge.Adrlitional rats were bled regularly throughout the study andmonitored for the appearance ofTMA-specific antibody; otherrats were terminated periodically during the 13-week exposureand examined for lung lesions. These serially terminated ratsshowed that TMA-induced lung lesions reached a maximum afterapproximately 2 weeks of exposure, but began to diminish thereafter.Rats bled regularly showed increasing TMA-specific antibodytiters through the first 6 weeks of exposure, after which antibodytiters diminished. Serum antibody levels rose sharply afterthe 13-week exposure ended and tapered off throughout the recoveryperiod. Rats terminated after 6.5 weeks of exposure showed adose-dependent increase in lung lesions and serum antibody.However, rats exposed to TMA for 13 weeks showed greatly reducedlung lesions and antibody titers. Rats exposed for 13 weeksand allowed to recover for 3 weeks showed increased antibodytiters but few lesions, even after a TMA challenge. Rats exposedfor 13 weeks and allowed to recover 38 weeks had reduced butstill significant antibody titers; however, no lung lesionswere noted even after a TMA inhalation challenge prior to termination.These results indicated that rats became tolerant to TMA andthat 13 weeks of exposure to TMA did not produce lesions ofany type, even after 38 weeks of recovery.