Toxicity Sudies of Acetone Administered in the Drinking Water of Rodents

Toxicity Studies of Acetone Administered in the Drinking Waterof Rodents. DIETZ, D. D., LEININGER, J. R., RAUCKMAN, E. J.,THOMPSON, M. B., CHAPIN, R. E., MORRISSEY, R. L., AND LEVINE,B. S. (1991). Fundam Appl. Toxicol 17, 347–360. Two- andthirteen-week toxicity studies were conducted using male andfemale F344/N rats and B6C3F1 mice. Animals were exposed tothe following concentrations of acetone in their drinking water:two-week studm 0; 5000; 10,000; 20,000; 50,000; or 100,000 ppmacetone. Thirteen-week rat and female mouse studies 0; 2500;5000; 10,000; 20,000; or 50,000 ppm acetone. Thirteen week malemice were exposed to 0; 1250; 2500; 5000; 10,000; or 20,000ppm acetone. Depressed body weight gain was restricted to the50,000 and 100,000 ppm exposure groups. Male and female miceexposed respectively to 20,000 or 50,000 ppm acetone for 2 weeksdeveloped hepatocellular hypertrophy. This change was not apparentafter 13 weeks of exposure although relative and alsolute liverweight was increased in high dose female mice. Bone marrow hypoplasiawas observed In 5/5 high dose (100,000 ppm) male rats duringthe 2-week studies. Treatment of male rats for 13 weeks resultedin a variety of mild and subtle hematological changes that oftenoccurred at relatively low levels of exposure (5000 ppm) andresembled those seen during the clinical condition of megaloblasticanemia Changes characteristic of hypogonadism (depressed spermmotility and cauda epididymal and epididymal weight and elevatedincidence of abnormal sperm) were observed in male rats raceiving50,000 ppm acetone for 13 weeks. The incidence and severityof a kidney laion that is morphologically similar to the spontaneouslyoccurring nephropathy among aging F-344 rats were increasedat 20,000 and 50,000 ppm acetone, respectively, in 13-week malerats. In summary, the effects of acetone were either subtlein nature or occurred during very high levels of exposure confirmingacetone's low level of toxicity. The daily levels of acetoneexposure were often several-fold greater than possibly encounteredby humans during the accidental consumption of contaminatedgroundwater (250 ppm; 5 mg/day) and frequently exceeded maximumlevels reported following acute toxic exposures (2,500 mg/kg).     

The Developmental Toxicity of Ethylene Glycol Diethyl Ether in Mice and Rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New ZealandWhite rabbits were dosed by gavage with ethylene glycol diethylether (EGdiEE) in distilled water during major organogenesis.Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50,150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19(0, 25, 50, or 100 mg/kg/day). Maternal clinical status wasmonitored daily during treatment. At termination (gd 17, mice;gd 30, rabbits), confirmed-pregnant females (22–24 pergroup, mice; 26–32 per group, rabbits) were evaluatedfor clinical status and gestational outcome; each live fetuswas examined for external, visceral, and skeletal malformations.In mice, no maternal mortality was observed, but maternal bodyweight gain during gestation and treatment, and at terminationwas reduced at 1000 mg/kg/day. The reduction of maternal bodyweight gain during gestation was secondary to embryo/fetal toxicity,i.e., reduced gravid uterine weight as a consequence of decreasedlitter size and fetal weight. The no-observed adverse effectlevel (NOAEL) for developmental toxicity was 50 mg/kg/day. At150 mg/kg/day the number of litters of mice with malformed fetuseswas increased. At 500 mg/kg/day fetal body weight was reduced,and malformation incidence was significantly increased. Exencephalyand fused ribs were observed most often. In rabbits, maternalbody weight was unaffected by treatment even though 6% maternalmortality was observed at 100 mg/kg/day. The developmental NOAELwas 25 mg/kg/day. Malformations were increased at 50 mg/kg/day,short tail, small spleen, fused sternebrae, and fused rib cartilagewere observed most often. In summary, oral administration ofEGdiEE to mice and rabbits during organogenesis produced profoundadverse developmental effects even in the absence of significantmaternal toxicity. Developmental effects in rabbits were morevaried.     

The Developmental Toxicity of Orally Administered Oxytetracycline in Rats and Mice

The Developmental Toxicity of Orally Administered Oxytetracyclinein Rats and Mice. MORRISSEY, R.E., TYL, R.W., PRICE, C.J., LEDOUX,T.A., REEL, J.R., PASCHKE, L.L., MARR, M.C, AND KJMMEL, C.A.(1986). Fundam. Appl. Toxicol. 7, 434-443. Timed-pregnant CDrats and CD-1 mice were dosed by gavage with oxytetracyclinehydrochloride (OXT) in corn oil on gestational days (gd) 6-15(0, 1200, 1350, or 1500 mg/kg/day for rats; 0, 1325, 1670, or2100 mg/kg/day for mice). Deaths among treated females occurredin a dose-related manner in all OXT dose groups (2-7%, mice;5-24%, rats), but no maternal deaths occurred in the vehiclecontrol groups. Significant dose-related decreases in maternalweight gain during treatment, as well as for corrected gestationalweight gain (i.e., maternal gestational weight gain minus graviduterine weight), were observed at all doses in rats but notin mice. Gravid uterine weight was reduced in a dose-relatedmanner only in mice, with the high-dose group significantlyreduced compared to the control group. At termination (gd 20,rats; gd 17, mice), the status of uterine implantation siteswas recorded and live fetuses were weighed. Fetuses were examinedfor external, visceral, and skeletal abnormalities. There wereno significant effects of OXT in either species on the incidenceof postimplantation loss (resorptions plus dead fetuses) ormalformations. In both species, there was a significant trendtoward reduced fetal body weight, and each group of rats receivingOXT was significantly reduced compared to the control group.Administration of OXT during organogenesis at doses exceedingthe therapeutic range for humans produced maternal and fetaltoxicity, but did not produce any treatment-related increasein malformations.     

Developmental Toxicity of Inhaled Methyl Ethyl Ketone in Swiss Mice

Developmental Toxicity of Inhaled Methyl Ethyl Ketone in SwissMice. Schwetz, B. A., Mast, T. J., Weigel, R. J., Dill, J. A.,and Morrissey, R. E. (1991). Fundam. Appl. Toxicol. 16, 742–748.Methyl ethyl ketone (MEK) is a widely used industrial solventto which there is considerable human exposure. To assess thepotential for MEK to cause developmental toxicity in rodents,groups of Swiss (CD-1) mice were exposed to 0, 400, 1000, or3000 ppm MEK vapors 7 hr/day on Days 6–15 of gestation.Groups consisted of about 30 bred females each. Exposure ofpregnant mice to these concentrations of MEK did not resultin overt maternal toxicity although there was a slight, treatment-relatedincrease in relative liver weight which was statistically significantin the 3000 ppm group. Mild developmental toxicity was observedin the 3000 ppm group in the form of a reduction in mean fetalbody weight. This reduction was statistically significant forthe males only, although the relative decrease from the controlvalues was the same for both sexes. There was no increase inthe incidence of resorptions or the number of litters with resorptionsamong mice exposed to MEK. There was no significant increasein the incidence of any single malformation, but several malformationswhich were not observed in the concurrent control group or thecontrols of contemporary studies were present at a low incidence—cleftpalate, fused ribs, missing vertebrae, and syndactyly. Therewas also a significant trend for increased incidence of misalignedsternebrae, a developmental variation. In summary, pregnantSwiss (CD-1) mice were relatively insensitive to the toxic effectsof MEK at the inhaled concentrations used in this study. However,the offspring of the mice exhibited significant signs of developmentaltoxicity at the 3000 ppm exposure level. Neither maternal nordevelopmental toxicity was observed at 1000 ppm MEK or below.     

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.     

Eicosanoid production and levels of newly characterized eicosanoid-forming enzymes in glomeruli and tubules of rat kidneys

Summary: We examined the production of prostaglandin (P0) E₂, 6-keto PGF_1α and thromboxane (Tx) B₂, the mass of cyclooxygenase (COX) isoenzymes and the activities of phospholipases A₂ and C in glomeruli, cortical tubules and medullary tubules of rat kidneys. Medullary tubules produced significantly greater amounts of PGE₂, 6-keto PGF1α. and TxB2 than glomeruli or cortical tubules. the most abundant eicosanoid in medullary tubules was 6-keto PGF1_α. By contrast, glomeruli and cortical tubules predominantly produced POE₂ (glomeruli > cortical tubules). Levels of COX 1 were markedly greater in medullary tubules than in glomeruli or cortical tubules. Glomeruli had significantly greater amounts of COX 1 than cortical tubules. Detectable amounts of COX 2 were not present in the three preparations. the activity of phospholipase (PL) A₂ against phosphatidyicholine (PC) was significantly greater in tubules (medullary tubules > cortical tubules) than in glomeruli. By contrast, there was a significant increase in the activity of PLA₂ against phosphatidylethanolamine (PE) in glomeruli as compared to tubules (medullary tubules > cortical tubules). the activity of PLC was the Weatest in medullary tubules. Glomeruli had significantly greater activity of PLC than cortical tubules. the order of magnitude for the total activity of the three phospholipases in membranes was medullary tubules> glomeruli> cortical tubules. the total production rate of POE₂, 6-keto PGF1α and TxB₂ was in parallel with the amount of COX 1 and the total activity of membranous phospholipases A₂ and C in the three preparations. In conclusion, there are differences in the production of PGE₂, 6.-keto PGF1α and TxB₂, the ainount of COX 1 and the activities of phospholipases A₂ andC among glomeruli, cortical tubules and medullary tubules of rat kidneys; and the different aspects of COX 1 and phospholipases A₂ and C have a key role in the control of eicosanoid production in the three preparations.