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.     

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropene on Fetal Development in Rats and Rabbits

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropeneon Fetal Development in Rats and Rabbits. HANLEY, T. R., Jr.,JOHN-GREENE, J. A., YOUNG, J. T., CALHOUN, L. L., AND RAO, K.S. (1987). Fundam. Appl. Toxicol. 8, 562–570. 1,3-Dichloropropene(DCP), which has found widespread use as a soil fumigant, wasevaluated for its potential effects on embryonal and fetal developmentin rats and rabbits. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropenefor 6 hr/day during gestation Days 6–15 (rats) or 6–18(rabbits). Exposure-related decreases in maternal weight gainand feed consumption were observed in rats at all treatmentlevels. Decreased weight gain was also observed among rabbitsat 60 and 120 ppm. A slight, but statistically significant,increase in the incidence of delayed ossification of the vertebralcentra in rats exposed in ulero to 120 ppm of DCP was consideredof little toxicologic significance in light of the maternaltoxicity observed at this exposure concentration. No evidenceof a teratogenic or embryotoxic response was observed in eitherspecies at any exposure level tested. Thus, it was concludedthat DCP was not teratogenic at exposure levels up to 120 ppmin either rats or rabbits.     

Incapacitation and Treatment of Rats Exposed to a Lethal Dose of Sulfuryl Fluoride

Incapacitation and Treatment of Rats Exposed to a Lethal Doseof Sulfuryl Fluoride. NIT-SCHKE, K., D., ALBEE, R.R., MATTSSON,J.L., AND MILLER, R.R. (1986). Fundam. Appl. Toxicol. 7, 664–670.Rats exposed to 4000 ppm sulfuryl fluoride (VIKANE^* gas fumigant,SO₂F₄) were incapacitated within 45 min and died within severalhours after exposure. Exposure to higher concentrations resultedin a shorter time to incapacitation and death occurred withinminutes. Treatment with calcium gluconate before exposure to4000 ppm SO2F2 for 45 min resulted in 80%survival. However,calcium gluconate did not alleviate SO₂F₄-induced convulsions.Administration of phenobarbital before or after exposure to4000 ppm SO₂F₄ for 45 min effectively reduced the frequencyand severity of convulsions and resulted in survival of allanimals. Exposure of rats to 10,000 ppm SO₂F₄ for 15 min followedby treatment with phenobarbital reduced the frequency of convulsionsand delayed death, but did not prevent death. Diazepam was lesseffective than phenobarbital while diphenylhydantoin had nobeneficial effect and, in fact, made the convulsions more severeand longer in duration. The results of this study indicate thatphenobarbital was effective in ameliorating the acute toxiceffects of an overexposure to SO₂F₄ in rats.     

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.     

Inhalation Oncogenicity Bioassay in Rats and Mice with Vinyl Fluoride

The purpose of this study was to assess the oncogenic potentialof vinyl fluoride in rats and mice when administered by inhalation.Male and female rats and mice were exposed to 0, 25, 250, or2500 ppm vinyl fluoride 6 hr per day, 5 days per week, for 2years (rats) or 18 months (mice). Slight body weight gain decrementswere noted in groups of vinyl fluoride-exposed rats and mice.No significant clinical signs of toxicity were noted other thanan increase in the incidence of palpable masses in the regionof the mammary gland in female mice exposed to vinyl fluoride.Survival was decreased in male rats and mice of the 250 and2500 ppm groups and female rats and mice of all vinyl fluoride-exposedgroups compared to controls. Urinary fluoride excretion, anindicator of vinyl fluoride metabolism, increased with concentrationand time although the dose relationship appeared to plateauat concentrations 250 ppm. Gross observations made at necropsyof rats supported histological observations of hepatic hemangiosarcoma,hepatocellular adenoma and carcinoma, hepatic foci of clearcell and basophilic alteration, hepatic sinusoidal dilatation,metastatic lung tumors, and Zymbal's gland tumors. Hepatic hemangiosarcomawas the sentinel lesion in rats. Gross observations made atnecropsy of mice supported histological observations of bronchioloalveolaradenoma and hyperplasia, hepatic hemangiosarcoma and hepatocellularhyperplasia with angiectasis and peliosis, and mammary glandadenocarcinoma and hyperplasia. Bronchioloalveolar adenoma appearedto be the sentinel lesion in mice. The spectrum of vinyl fluoride-inducedtumors is similar to that induced by other monohaloethylenesin rats and mice. Under the conditions of this study, vinylfluoride was carcinogenic in male and female rats and mice atconcentrations greater than or equal to 25 ppm.     

Acute Effects of 10-Minute Exposure to Hydrogen Fluoride in Rats and Derivation of a Short-Term Exposure Limit for Humans

A series of acute inhalation exposures of female rats was conducted with hydrogen fluoride (HF) to establish a concentration–response curve for nonlethal exposures. Durations of 2 and 10 min were used to simulate possible short-term exposures. Concentrations of HF ranged from 593 to 8621 ppm for 2-min exposures and from 135 to 1764 ppm for 10-min exposures. Additional exposures were performed for 60 min at 20 and 48 ppm HF for comparison to existing Emergency Response Planning Guidelines. Animals were evaluated on the day after exposure for changes in parameters of bronchoalveolar lavage, pulmonary function, hematology, serum chemistry, body weight, organ weights, and histopathology. Most exposures were performed with orally cannulated animals to bypass absorption of HF in the nose and achieve maximum delivery of HF to the lower airways. One of the primary uses of the resulting data was to estimate a concentration to which most people could be exposed for 10 min without severe or irreversible health effects. This level was 130 ppm. It was predicted that irritation would occur at this concentration, but the effects on the respiratory tract would not be “serious” and would be expected to be reversible. The results of this experiment and the subsequent analysis of the data provide an important aid in the planning of responses to an accidental release of HF.     

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.     

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.     

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.     

Developmental Toxicity Evaluation of Sodium Fluoride Administered to Rats and Rabbits in Drinking Water

Sodium fluoride (NaF; Cas No. 7681-49-4) is used in fluoridatingmunicipal water supplies, resulting in chronic exposure of millionsof people worldwide. Because of a lack of pertinent developmentaltoxicity studies in the literature, sodium fluoride was administeredad libitum in deionized/filtered drinking water (to mimic humanexposure) to Sprague-Dawley-derived rats (26/group) on GestationDays (GD) 6 through 15 at levels of 0, 50, 150, or 300 ppm andNew Zealand White rabbits (26/group) on GD 6 through 19 at levelsof 0, 100, 200, or 400 ppm. Higher concentrations via drinkingwater were not practicable due to the poor palatability of sodiumfluoride. Drinking water (vehicle) contained less than 0.6 ppmsodium fluoride (limit of detection) and sodium fluoride contentof the feed was 12.4 ppm fluoride (rats) and 15.6 ppm fluoride(rabbits). Maternal food, water, body weights, and clinicalsigns were recorded at regular intervals throughout these studies.Animals were killed on GD 20 (rats) or 30 (rabbits) and examinedfor implant status, fetal weight, sex, and morphological development.In the high-dose group of both studies there was an initialdecreased maternal body weight gain which recovered over timeand a decreased water consumption—attributed to decreasedpal atability. No clear clinical signs of toxicity were observed.Maternal exposure to sodium fluoride during organogenesis didnot significantly affect the frequency of postimplantation loss,mean fetal body weight/litter, or external, visceral or skeletalmalformations in either the rat or the rabbit. The NOAEL formaternal toxicity was 150 ppm sodium fluoride in drinking water({small tilde}18 mg/kg/day) for rats, and 200 ppm ({small tilde}18mg/kg/day) for rabbits. The NOAEL for developmental toxicitywas 300 ppm sodium fluoride ({small tilde}27 mg/kg/day) forrats and 400 ppm ({small tilde}29 mg/kg/day) for rabbits administeredduring organogenesis in drinking water. The total exposure tofluoride (mg F/kg body weight/day from food and drinking watercombined) in the mid- and high-dose groups for both specieswas >100-fold higher than the range at 0.014–0.08 mgF/kg/day estimated for a 70-kg person from food and fluoridated(1 ppm) drinking water.     

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.     

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.     

The Effects of Love Canal Soil Extracts on Maternal Health and Fetal Development in Rats

The Effects of Love Canal Soil Extracts on Maternal Health andFetal Development in Rats. SILKWORTH, J.B., TUMASONIS, C, BRIGGS,R.G., NARANG, A.S., NARANG, R.S., REJ, R., STEIN, V., MCMARTIN,D.N., AND KAMINSKY, L.S. (1986). Fundam. Appl. Toxicol. 7,471-485.The effects of a solvent extract of the surface soil of theLove Canal chemical dump site, Niagara Falls, New York, andof a natural extract, or leachate, which is drained from thecanal for treatment, on the maternal health and fetal developmentwere determined in rats. The solvent extract, which was contaminatedwith 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) at 170ppb and numerous other chlorinated organic compounds with theprimary identified components being the isomers of benzenehexachloride(BHC), was dissolved in corn oil and administered by gavageto pregnant rats at 0,25,75, or 150 mg crude extract/kg/dayon Days 6-15 of gestation. A 67% mortality was observed at thehighest dose. The rats were sacrificed on Day 20. Dose-relatedincreases in relative liver weight accompanied by hepatocytehypertrophy were observed at all dose levels. Fetal birthweightwas decreased at 75 and 150 mg extract/kg/day. No major treatment-relatedsoft tissue or skeletal malformations, except for delayed ossification,were observed. Based on literature values for BHC, all of theobserved toxicity could be accounted for by the BHC contaminantsof the extract. The crude organic phase of the leachate wasadministered to pregnant rats at 0, 10, 100, or 250 mg/kg/dayas described above. Maternal weight gain decreased at 100 and250 mg/kg/day, accompanied by 5 and 14% maternal mortality,and 1 and 3 dead fetuses, respectively. Early resorptions andthe percentage of dead implants increased whereas fetal birthweightswere decreased at 250 mg/kg/day. No major treatment-relatedsoft tissue or skeletal malformations, except for delayed ossification,were observed. The primary components of the complex leachateby mass were tetrachloroethanes; however, 2,3,7,8-TCDD, whichwas present at 3 ppm, probably accounted for all the observedtoxicity.     

Subacute Inhalation Exposure of Rats to 1,6-Hexamethylene Diisocyanate With Recovery Period

In this subacute inhalation toxicity study of 1,6-hexamethylene diisocyanate (HDI), groups of 10 male and 10 female Sprague-Dawley rats were exposed to 0, 0.005, 0.0175, or 0.150 ppm HDI vapor, 5 h/ /day, 5 days/ /wk for 15 exposure days and included animals sacrificed 2 wk postexposure. The purpose was to characterize the HDI-induced effects and their reversibility, and to determine a no-observed-adverse-effect level (NOAEL). No compound-related effects were found for body weights, clinical chemistry, urinalysis, hematology, and organ weights. Thus, no evidence of systemic toxicity was found in this study. The exposure-related findings were restricted to the portal of entry, the respiratory tract. Transient signs of sensory irritation were observed after the daily exposure periods, but the principal findings were the histopathologic changes of the nasal epithelium. Generally, an anterior to posterior gradient of incidence and severity was found, and the changes were characterized as acanthosis, erosion, hyperkeratosis, epithelial cell hyperplasia, chronic active inflammation, squamous metaplasia, ulceration, transitional epithelial cell degeneration, goblet-cell hyperplasia, and degeneration of the olfactory epithelium. Varying degrees of concordance between exposure concentration and incidence and/or severity of the histopathologic changes were found. During a 2-wk recovery period, a tendency toward recovery was evident for tissue changes in the nasal cavity. A NOAEL of 0.0175 ppm HDI was determined.     

Subchronic Inhalation Exposure to Acetone Vapor and Scheduled Controlled Operant Performance in Male Rats

Groups of adult male rats (10/group) were used to assess whether subchronic inhalation exposure to 0, 1000, 2000, or 4000 ppm of acetone vapor altered schedule-controlled operant performance. Rats were exposed to acetone vapor for 6 h/day, 5 days/wk, for a 13-wk period. Extensive training prior to the exposure series established a stable baseline of lever-pressing on a multiple fixed-ratio-fixed-interval (FR 20-FI 120 s) schedule of food presentation. Operant sessions occurred prior to each daily exposure to avoid confounding the detection of enduring behavioral effects with transient acute effects. FI response rate, FI index of curvature, and FR running rate of response were not affected during or after the 13-wk exposure series. FR post-reinforcement pause duration for the control group increased during the course of the study more than that of the 2000 ppm and 4000 ppm groups, which changed only slightly relative to pretreatment baseline. Based on the performance of historical controls that had FR pause durations similar to those of acetone-treated groups, the differences in FR pause duration were probably due to drift of the concurrent control group and were not related to acetone treatment. Prolonged exposure to up to 4000 ppm acetone vapor does not appear to have enduring effects on nervous system functions that mediate the performance of a complex, learned task.     

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.     

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