The Developmental Toxicity of Diethylene Glycol Dimethyl Ether in Mice

The Developmental Toxicity of Diethylene Glycol Dimethyl Etherin Mice. PRICE, C. J., KIMMEL, C. A., GEORGE, J. D., AND MARR,M. C. (1987). Fundam. Appl. Toxicol. 8, 115–126. Diethyleneglycol dimethyl ether (diEGdiME) is structurally related toseveral compounds which produce reproductive and developmentaltoxicity, including teratogenicity in laboratory animals. Inthe present study, diEGdiME (0, 62.5, 125, 250, or 500 mg/kg/day)was administered by gavage in distilled water to timed-pregnantCD-1 mice during major organogenesis [gestational days (gd)6–15]. Clinical status of treated females was monitoreddaily during treatment and on gd 17. At sacrifice (gd 17), pregnancywas confirmed by uterine examination for 20–24 dams pergroup; each live fetus was examined for external, visceral,and skeletal malformations. No maternal deaths, morbidity, ortreatment-related clinical signs were observed. Reduced maternalweight gain during treatment at 250 mg/kg/day was primarilyattributed to compromised pregnancy status resulting in reducedgravid uterine weight. Maternal weight gain during gestationcorrected for gravid uterine weight, and relative liver weight(% body weight) were not affected. Average fetal body weight/litterwas significantly reduced at 125 mg/kg/day. The percentageof postimplantation loss/litter (5, 8, 7, 12, and 50% for controlthrough high dose) and the percentage of malformed live fetuses/litter(0.4, 0, 2, 24, and 96%) were significantly increased at 250mg/kg/day. Developmental defects involved primarily the neuraltube, limbs and digits, craniofacial structures, abdominal wall,cardiovascular system, urogenital organs, and both the axialand appendicular skeleton. In summary, oral administration ofdiEGdiME during major organogenesis did not produce any distinctivesigns of maternal toxicity, but did produce selective and profoundadverse effects upon fetal growth, viability, and morphologicaldevelopment at 125 mg/kg/day.     

Diesel Exhaust Is Not a Pulmonary Carcinogen in CD-1 Mice Exposed under Conditions Carcinogenic to F344 Rats

Differences among laboratory animal species in the pulmonarycarcinogenicity of chronic inhalation exposure to diesel exhausthave raised several important interpretive issues. Under similarheavy exposure conditions, it is clear that diesel exhaust isa pulmonary carcinogen in rats, but not in Syrian hamsters.Previous reports give conflicting views of the response of mice,which is presently considered equivocal. This report describescarcinogenicity results from a bioassay of CD-1 mice conductedin parallel with a previously reported bioassay of F344 rats(Mauderly et al. (1987) Fundam. Appl. Toxicol. 9, 208–221).Exposure to whole diesel exhaust 7 hr/day, 5 days/week for 24months at soot concen trations of 0.35, 3.5, or 7.1 mg/m³ causedaccumulations of soot in mouse lungs similar to those in lungsof rats and, like the results from rats, did not significantlyaffect survival or body weight. In contrast to the dose-relatedneoplastic response of rats, however, the exposures of micedid not increase the incidence of lung neoplasms. This findingis consistent with other data showing that mice, as well asSyrian hamsters, differ from rats in their lung neoplastic andnonneoplastic responses to heavy, chronic inhalation exposureto diesel exhaust soot and several other particles. Althoughrodents serve as useful indicators of potential human carcinogenichazards, it is not yet clear which, if any, rodent species havelung neoplastic responses that are useful for quantitative predictionsof human lung cancer risk from chronic inhalation of poorlysoluble, respirable particles.     

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.     

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronically by Inhalation

Diesel Exhaust Is a Pulmonary Carcinogen in Rats Exposed Chronicallyby Inhalation. MAUDERLY, J. L., JONES, R. K., GRIFFITH, W. C.,HENDERSON, R. F., AND MCCLELLAN, R. O. (1987). Fundam. Appl.Toxicol 9, 208–221. Male and female F344 rats were exposed7 hr/day, 5 day/week for up to 30 months to automotive dieselengine exhaust at soot concentrations of 0.35, 3.5, or 7.0 mg/m³or were sham-exposed to clean air. Rats were terminated at 6-monthintervals to measure lung burdens of diesel soot and for histopathology.Other rats either died or were terminated after 30 months ofexposure. Lungs were fixed, sectioned into 3-mm slices, andexamined by a dissecting microscope to detect tumors. Lesionswere stained and examined by light microscopy. Survival andbody weight were unaffected by exposure. Focal fibrotic andproliferative lung disease accompanied a progressive accumulationof soot in the lung. The prevalence of lung tumors was significantlyincreased at the high (13%) and medium (4%) dose levels abovethe control prevalence (1%). Four tumor types, all of epithelialorigin, were observed: adenoma. adenocarcinoma, squamous cyst,and squamous cell carcinoma. Logistic regression modeling demonstrateda significant relationship between tumor prevalence and bothexposure concentration and soot lung burden. These results demonstratethat diesel exhaust, inhaled chronically at a high concentration,is a pulmonary carcinogen in the rat.     

His Bundle Ablation with the Laser Thermal Probe ("Hot Tip"): A Feasibility Study

Successful percutaneous ablation of the bundle of His requires accurate localization together with delivery of the minimum effective energy to avoid unwanted effects. The energy output from laser sources can be controlled very precisely but is not easily directed to the bundle of His using conventional fiber optics. The laser thermal probe ("hot tip") consists of an optical fiber and a terminal metal cap that is rapidly heated during energy delivery. When applied to cadaver hearts at energies of 100-150 joules (10 watts for 10-15 seconds) the 2.0-mm diameter peripheral artery probe was able to damage the bundle of His without extensive surrounding damage. The right ventricular free wall and interventricular septum were perforated during some applications at these energies leaving a tract with a diameter of less than 2.0 mm. The atrioventricular (AV) membranous septum, Foramen Ovale, right atrial appendage, and septal leaflet of the tricuspid valve were more resistant at these energy levels and perforations were always less than 1.0 mm in diameter. The probe was modified for use during electrophysiological studies and good quality unipolar electrograms were recorded from the metal cap confirming that the probe could be accurately positioned adjacent to the bundle of His. The laser thermal probe deserves further study as a "self directing" ablation tool.