Search

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

Iodinated radiographic contrast media have traditionally been contraindicated in patients with sickle cell disease because their high osmolality may induce osmotic shrinkage of red blood cells, impair blood flow through the microcirculation, and precipitate or exacerbate a sickle cell crisis. This study investigated that concept by comparing the hematological and rheological effects in vitro of four X-ray contrast media of differing osmolalities: Visipaque (290 mOsm/kg), Hexabrix (600 mOsm/kg), Omnipaque (844 mOsm/kg), and RenoCal-76 (1940 mOsm/kg). Blood was tested from 10 normal and 10 sickle cell donors at drug concentrations of 0, 1, 10, and 30% w/v in an attempt to approximate the relative concentrations of contrast medium to blood that might occur during the bolus-injection and circulation-diluted phases of drug administration. Parameters evaluated included hematology, red cell morphology, and red cell flow resistance through a micropore filter to approximate the microcirculatory effects. Significant hematological effects for both normal and sickle cell donors included a concentration dependent decrease in hematocrit and MCV, and increase in MCHC, all of which varied directly with the osmolality of the contrast media in the order of RenoCal-76 > Omnipaque > Hexabrix > Visipaque. The contrast media had minor effects on red blood cell morphology except for RenoCal-76, 10-30% in which marked echinocytosis was observed. There was no significant increase in the number of irreversibly sickled cells in donors with hemoglobin S. Filterability of red cell suspensions through capillary size pores was impaired in both normal and sickle cell samples in direct proportion to the osmolality of the contrast media, as listed above. Filterability effects were greater for sickle cells than for normal red cells. Visipaque, which was closest to isotonicity, had little effect on red cell volume and had no significant effect on filterability of normal or sickle cells. These results suggest that microcirculatory impairment following infusion of contrast media may occur in sickle patients because of the unusual rheological sensitivity of HbSS red cells, and may be avoided by choice of an isotonic medium.

5-Vinyl-2-norbornene (VNB: CAS Number 3048-64-4) is an industrial chemical with a potential for exposure to the vapor. To determine any hazards from repeated exposure to the vapor a subchronic exposure study was conducted in which male and female Sprague Dawley rats were exposed to VNB vapor for 6 hours per day, 5 days per week for 14 weeks at mean concentrations of 0, 5, 25.5, and 152 ppm. Subgroups at 0 and 152 ppm were kept for a 4-week post-exposure recovery period. This study was preceeded by a 9-day repeated vapor study in which male and female rats were exposed to mean concentrations of 50, 147, and 352 ppm. In both the 9-day and subchronic studies there were no significant exposure-related effects with respect to signs, mortality, body weights, serum chemistry, or urinalysis. The only hematological effect was an increase in the mean corpuscular volume and mean corpuscular hemoglobin in male rats of the 147 and 352 ppm groups. There were exposure-related increases in liver weights with the 9-day st...

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.

Rationale and Objectives. The purpose of the study was to determine if airway instillation of iodinated nanoparticles results in contrast material enhancement of tracheobronchial lymph nodes in dogs. Materials and Methods. Eight dogs underwent intrabronchial instillation of iodinated nanoparticles; six dogs received 900 mg each, and two dogs received 450 mg each. Spiral computed tomography (CT) was then performed 2–34 days later. Results. CT scans obtained 2 days after instillation showed the presence of contrast material within the lung parenchyma but no nodal enhancement. Scans obtained 6–34 days after instillation showed enhancement of the right, left, and middle tracheobronchial lymph nodes (analogous to the mediastinal nodes in humans). Mean nodal attenuation on CT images was 117 HU ± 43, and the mean nodal volume was 129 mm3 ± 113. Histologic specimens of the nodes showed macrophage hyperplasia. Conclusion. Iodinated nanoparticles instilled into small airways are transported to the tracheobronchial lymph nodes, where they result in contrast enhancement.

5-Ethylidene-2-norbornene (ENB) is an industrial chemical whose physical properties indicate a likelihood for vapor exposure to humans. The potential for target organ or cumulative toxicity was investigated in rats exposed for 6 h per day for 9 days over an 11-day period, or 66 or 67 days over 14 weeks; 4-week recovery animals were added to the 14-week study. Mean analytically measured ENB vapor concentrations (±SD) were 52 ± 1.5, 148 ± 2.3 and 359 ± 4.2 ppm for the 9-day study and 4.9 ± 0.14, 24.8 ± 1.23 and 149 ± 4.40 ppm for the subchronic study. There were no mortalities, and clinical signs were limited to periocular swelling and/or encrustation, and urogenital area wetness. Body weight gain was decreased in the 9-day 359 ppm females and in the subchronic 24.8 and 149 ppm males. A minimal macrocytic anemia was present in subchronically exposed males, which resolved during the recovery period. In the 9-day study increased liver weight was associated with minimal centrilobular hepatocytomegaly and cytoplasmic basophilia with no degenerative or serum biochemical liver function changes, suggesting an adaptive response. Only relative liver weights were increased in the subchronic 149 ppm males, and no histopathological findings were observed. Principal target organ effects were to the thyroid gland, which showed an exposure concentration-related, but not exposure time-related, depletion of follicular colloid that resolved during the recovery period, together with light microscopic evidence for a hypertrophic and hyperplastic response in the follicular epithelium that resolved more slowly. The thyroid colloid depletion was a graded effect without a clear no-effect concentration, but was not accompanied by any clinical or clear biochemical evidence for thyroid dysfunction. A no-effect concentration of 4.9 ppm was established for the follicular cytological effects. © 1997 John Wiley & Sons, Ltd.

Four groups of Sprague-Dawley rats (15 rats/sex/group) were exposed by whole body to analytically measured concentrations of 0 (control), 0.23, 1.25, or 5.8 ppm bis/2-(dimethylamino)ethyl ether (DMAEE) vapor for 6 h/day, 5 days/wk, for 14 wk. Ten rats/sex/group were euthanized after the exposure regimen, and 5 rats/sex/group were euthanized after a 6-wk recovery period. An additional 3 rats/sex, exposed to 0 and 5.8 ppm, were sequentially sacrificed following 1, 3, or 5 exposures for electron microscopic evaluation. The only systemic toxicity was reduced body weight gain for the 5.8 ppm group throughout the exposure regmen. Clinical signs of ocular and nasal tract irritation (swollen eyelids and periocular and perinasal encrustation) were observed, primarily in the 5.8 ppm group, during the exposure and recovery periods. An ophthalmic examination, following 13 wk of exposure, revealed keratitis in males from the 5.8 ppm group and females from the 1.25 and 5.8 ppm groups. At necropsy, diffuse corne...

Glutaraldehyde (GA: CAS Number 111-30-8) is a widely used industrial chemical and biocide from which skin contact may occur. The potential for local and systemic toxicity by repeated skin contact was investigated in Fischer 344 rats using occluded epicutaneous applications of 2.5, 5.0, and 7.5% aqueous GA solutions at a dose volume of 2.0 ml/kg/day, 6 h/day, for 20 applications over a 26 day period. This was equivalent to 50, 100, and 150 mg GA/kg/day. Controls received filtered water at 2.0 ml/kg/day. There were no treatment-related mortalities or clinical signs of systemic toxicity. Local skin irritation, mainly erythema and edema, was minimal and present only intermittently during the treatment period, and resolved in 4-week recovery animals. There were slight decreases in body weight, body weight gain, and food consumption. A gender-related discrepancy in water consumption, apparently increased in males and decreased in females, was probably related to proximity to the animal holding room air ...

Male and female New Zealand White rabbits were exposed to 0.0,0.05,0.1, or 0.2 ml/kg of undiluted methyldimethoxysilane (MDMS), corresponding to 43, 85, or 171 mg/kg, applied under occlusive dressing to the clipped dorsal trunk skin for nine doses over an 11 day period. Five animals/group/gender (10/gender in the 85 mg/kg/day group) were euthanized at the end of the exposure period. Five animals/group/gender from the high-dose and control groups were retained for a 2 week recovery period and then euthanized. The only abnormal findings involved the treated skin. Clinical observations included mild to moderate irritation of the treated skin, affecting mainly high-dose group animals euthanized immediately after the exposure period, with females being slightly more sensitive. Significant gross and microscopic lesions were seen in the treated skin of animals receiving 0.1 ml/kg/day and higher. Gross lesions consisted of erythema, ecchymoses, exfoliation, excoriation, fissures, ulceration, and necrosis....

Assessment of the Developmental Toxicity of Ethylene Glycol Applied Cutaneously to CD-1 Mice. Tyl, R. W., Fisher, L. C., Kubena, M. F., Vrbanic, M. A., and Losco, P. E. (1995). Fundam. Appl. Toxicol. 27, 155-166. Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body exposure to an aerosol at high concentrations, but results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG on Gestational Days (GD) 6 through 15, 6 hr/day by occluded cutaneous application at 0, 12.5, 50, or 100% (undiluted) EG (0.1 ml/animal, equivalent to ∼0, 404, 1677, or 3549 mg/kg/day, respectively) or by gavage on GD 6 through 15 at 3000 mg/kg/day [10 ml/kg, positive control gavage group (PCGG)], 30 females/group. Dams were weighed and evaluated daily (including application site) for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and paired kidneys were weighed; kidneys of 0 and 100% and the PCGG were examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For cutaneously exposed dams, there was no treatment-related maternal toxicity, no differences in pre- or postimplantation loss or in fetal body weights/litter, and no increased incidences of any fetal malformations. Two skeletal variations, increased at 100%, may represent effects of restraint stress and/or findings due to chance. In the PCGG, 8 females (26.7%) died, water consumption was increased, fetal body weights/litter were reduced, and fetal malformations and variations were increased. PCGG kidneys exhibited tubular nephrosis and tubular cell degeneration, with no oxalate crystals, documenting renal toxicity at this oral dose in mice. Minimal-grade renal tubular lesions observed in 3 mice (of 30) at 100% EG may represent treatment-related or incidental findings. Therefore, exposure of pregnant CD-1 mice to 0, 12.5, 50, or 100% EG during organogenesis by occluded cutaneous application resulted in minimal or no observable maternal or developmental toxicity at 100% (∼3549 mg/kg/day), the NOEL.

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body (WB) exposure to aerosol (1000-2500 mg/m3). The WB results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG aerosol (MMAD 2.6 +/- 1.7 microns) on Gestational Days (GD) 6 through 15, 6 hr/day, by nose-only (NO) (0, 500, 1000, or 2500 mg/m3) or WB exposures (0 or 2100 mg/m3, as positive control), 30/group. Five additional "satellite" females each at 2500 mg/m3 NO and 2100 mg/m3 WB were exposed on GD 6 for measurement of EG on fur. Control environments were water aerosol (4200 mg/m3 for NO; 2700 mg/m3 for WB). Females were weighed and evaluated for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and kidneys (2) were weighed, with kidneys examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For NO dams, kidney weights were increased at 1000 and 2500 mg/m3; no renal lesions and no other treatment-related maternal toxicity were observed. There were no effects on pre- or postimplantation loss; fetal body weights/litter were reduced at 2500 mg/m3. At 2500 mg/m3, incidences of fused ribs and skeletal variations were increased. The 2500 mg/m3 NO satellite animals had approximately 330 mg/kg extractable EG. The WB group exhibited maternal and developmental toxicity including increased fetal skeletal malformations and variations, confirming previous results, with 1390 mg/kg extractable EG on fur. Therefore, exposure of CD-1 mice to a respirable EG aerosol during organogenesis by NO inhalation resulted in minimal maternal toxicity at 1000 and 2500 mg/m3 and developmental toxicity at 2500 mg/m3. The NOAEL was 500 mg/m3 NO for maternal and 1000 mg/m3 NO for developmental toxicity. This study supports the interpretation of the initial EG WB results as due to systemic exposure from noninhalation routes since limiting noninhalation routes prevented almost all of the effects (including teratogenicity) observed in mice after WB exposure.

Prior aerosol inhalation studies on heavier molecular weight members of this series of ethylene oxide/propylene oxide (EO/PO) polymers have demonstrated that the lung is the primary target organ in rats. These studies extended the toxicological data on the lower molecular weight (MW) members (970 and 1700) of this series. In the present group of studies, the 4-hr acute LC50 value (95% confidence limits) for the 970 MW polymer (U-260) was determined to be 4770 (4260–5350) mg/m3 for the combined sexes of Sprague-Dawley rats. A previous study had determined the LC50 value for the 1700 MW polymer (U-660) to be 4670 (4090–5320) mg/m3 in Wistar rats. Repeated exposure studies were also conducted on both polymers, in which Fischer 344 rats were exposed for 6 hr/day, 5 days/week, for 9 exposures. For U-660, repeated exposure to mean concentrations of 504, 982, or 2460 mg/m3 produced total mortality at 2460 mg/m3, while signs of ocular and nasal irritation, respiratory difficulties, and reduced body weight...

BACKGROUND: SCH 206272, a neurokinin 1, 2, and 3 receptor antagonist, administered to beagle dogs results in testicular toxicity. Therefore, a series of experiments were conducted to determine whether this observed toxicity was associated with changes in reproductive hormones and hypothalamic gonadotrophin releasing hormone (GnRH) levels. METHODS: Male beagle dogs were administered 30 mg/kg SCH 206272 for up to 7 days. Blood samples were collected at the end of the dosing period for reproductive hormone analysis. Male reproductive organs were stained with hematoxylin and eosin and the hypothalamus was stained for GnRH. RESULTS: Intact male dogs exhibited SCH 206272related decreases in pulsatility and magnitude of luteinizing hormone (LH) and testosterone, which were associated with seminiferous tubule degeneration, oligospermia, and epithelial atrophy in the prostate gland. Neutered dogs also exhibited SCH 206272-related decreases in LH and FSH. In a subsequent reversibility study, intact male dogs exhibited decreased LH, testosterone, and FSH, which exhibited recovery by 2 weeks post-dosing; however, seminiferous tubule degeneration and oligospermia did not exhibit recovery by 2 weeks post-dosing. Dogs administered SCH 206272 also exhibited an increase in mean number of GnRH-containing neurons in the hypothalamus and an increase in GnRH mRNA/neuron, which exhibited recovery by 2 weeks post-dosing. CONCLUSIONS: SCH 206272-dosed dogs exhibited rapid decreases in reproductive hormones and subsequent testicular pathology. Collectively, these changes in hormone levels suggest that the observed SCH 206272-related reproductive tract findings are the result of alterations in hypothalamic–pituitary–gonadal function. However, a direct effect on the testes cannot be definitively ruled out. Birth Defects Res (Part B) 89:517–525, 2010. r 2010 Wiley-Liss, Inc.

This report describes the findings of preclinical testing of SCH 351591, a selective phosphodiesterase 4 inhibitor, in CD-1 mice over a wide range of doses, in which the heart and reproductive organs of both sexes demonstrated toxic effects. Repeat-dose toxicity studies assessed 5, 15, 50, 100, 200, 400, and 800 mg/kg/day, orally by gavage, for one or three months. Findings included higher testes and ovary weights and lower uterus weights (≥200 mg/kg), small ovaries/uterus (≥400 mg/kg), and histopathologic changes of large corpora lutea and ovarian atrophy at 200 and 800 mg/kg, respectively. In addition, chronic myocardial inflammation of the heart base occurred at 100 mg/kg. Vaginal staging of the estrous cycle revealed persistent diestrus. There was no histopathologic correlate or morphometric change to explain higher testes weights. A pilot fertility and early embryonic developmental toxicity study assessing doses of 100, 200, 400, and 800 mg/kg/day produced complementary results. Females had prolonged or abnormal estrous cycles, fewer successful pregnancies, increased ovarian corpora lutea, and decreased size of live litters owing to fetal resorptions. Male fertility was not affected. However, males had a 25% increase in testes weights at all doses. The pharmacology of specific PDE4 isoenzymes may explain both the reproductive and cardiac findings.

SCH 206272, an antagonist of neurokinin receptors 1, 2, and 3, was administered orally by gavage for 1 month to 8- to 10-month-old dogs at doses of 0, 15, 30, or 60 mg/kg, and to 6-week-old rats at doses of 0, 30, 100, or 300 mg/kg. The most important changes occurred in the reproductive tract of the dogs at all doses. Absolute and relative group mean organ weights for the testes, prostate gland, epididymides, ovaries, and uterus were 33–86% lower than concurrent controls in groups receiving SCH 206272. Organ weight changes were not dose-related. Microscopic changes that correlated with the organ weight changes occurred in all groups receiving SCH 206272. For males, they included minimal to severe atrophy of the testes, epididymides, and prostate gland. In addition, the epididymides exhibited severe oligospermia or aspermia, minimal epithelial apoptosis and mild epithelial vacuolation. In female dogs, the ovaries and uteri appeared immature. Microscopic changes were similar in incidence and severity in dogs receiving 30 or 60 mg/kg, but were slightly less in dogs receiving 15 mg/kg. In contrast, similar findings were not observed in the reproductive tract of male or female rats, despite overlapping systemic, hypothalamic, and pituitary gland concentrations of SCH 206272.

NC100100 produces marked vascular enhancement (for over 10 minutes) and better visualization of the normal blood flow in canine prostates. Contrast-enhanced ultrasound imaging in CAI mode (2D as well as 3D) matched the pathological measurements of ablation lesion and CTVS tumor sizes and location well. While free hand 3D CAI provided the best visualization of focal abnormalities, measuring the actual tumor size in this mode was limited by the inherent geometric uncertainties of the reconstruction technique. Ultrasound contrast improves the delineation of lesions as small as 4×5 mm (confirmed by pathology) and enables new lesions to be identified. The latter is clinically very important, since it opens up the possibility of reducing the currently very high rate of blind biopsies performed in prostate studies.2,3,4,5,6

Spontaneous hypospadias is seldom observed in rats in contrast to its occurrence in 1 out of 250 human births. Ziracin, an antibacterial of the everninomycin class under development for serious enterococcal, staphylococcal, and streptococcal infections, caused anomalies of the external genitalia in F1 female rats and decreased reproductive performance. To characterize the urogenital malformations and determine the period of sensitivity to the effects of Ziracin during development, pregnant rats (F0) were administered 60 mg/kg IV of Ziracin from GD6 to LD21, GD6 to 13, GD14 to the last day of gestation or LD0 to 21. Controls received saline or placebo from GD6 to LD21. Ziracin-induced changes occurred in F1 rats exposed from GD6 to LD21 and GD14 to the last day of gestation, indicating that the period of sensitivity to Ziracin was from GD 14 to the last day of gestation. The urogenital abnormalities consisted of cranial displacement of the urethral opening within the vagina from its normal location at the tip of the genital tubercle. When the urethrovaginal junction occurred at the distal third of the vagina, it created an urogenital cloaca. As a result, ascending infections were seen in the urinary and genital tract. No differences in survivability, body weight, and date of vaginal opening were observed in F1 females. The estrous cycles were slightly prolonged. The mating and fertility indices were decreased as a result of the urogenital anomalies. The mammary glands of pregnant F1 females were underdeveloped, thus F2 pups from affected F1 females had a decreased survival rate. Although the cause of these effects is not known, the findings are consistent with a potential hormonal mechanism.

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.

This study evaluated the utility of a new animal model for prostate cancer imaging using a new ultrasonographic contrast agent (Sonazoid [NC100100]; Amersham Health, Oslo, Norway), for prostate cancer detection.Twenty-four dogs had a canine transmissible venereal sarcoma cell line injected (50 million cells/mL) directly into the prostate, producing a neoplasm in 15 to 40 days. Transrectal ultrasonography was performed in power Doppler mode on 8 dogs (phase I) and in gray scale phase inversion harmonic imaging mode on 16 animals (including control animals without tumors; phase II). Evaluations were repeated after intravenous injections of the contrast agent (dose, 0.00625-0.20 microL/kg). Histopathologic examination was performed after each study. For the phase II experiments, sensitivity, specificity, and accuracy were calculated.The contrast agent improved visualization of the prostate cancer vascularity and delineation of tumor size and shape in both power Doppler and phase inversion harmonic imaging modes. Canine transmissible venereal sarcoma tumors ranging from 3 x 5 to 40 x 50 mm were detected. The accuracy for detecting the number of prostate tumors increased (in phase II) from 67% to 87% with the addition of the contrast agent. Histopathologic examination confirmed the ultrasonographic findings and revealed typical canine transmissible venereal sarcoma cells infiltrating the prostate with moderate neovascularity.The novel canine tumor model was useful for evaluating ultrasonographic prostate imaging techniques. Improved detection of prostate tumors in dogs was possible with gray scale phase inversion harmonic imaging of the contrast agent. The accuracy of lesion detection increased from 67% to 87%.

Glutaraldehyde (GA) has a wide spectrum of industrial, scientific and biomedical applications. Its potential to produce chronic toxic and/or oncogenic effects was investigated in Fischer 344 rats (100/sex/group) given GA in drinking water for a maximum of 104 weeks. GA concentrations were 0 (control), 50,250 and 1000 ppm, resulting in average daily GA consumptions, respectively, of 0, 4, 17 and 64 mg/kg for males and 0, 6, 25 and 86 mg/kg for females. Interim euthanasia (10/sex/group) was performed at 52 and 78 weeks. Parameters evaluated were clinical signs, body weight, food and water consumption, hematology, serum chemistry, urinalysis, organ weights, gross and microscopic pathology. There were no treatment-related effects on mortality. Absolute body weights and body weight gains of the 250 and 1000 ppm males and females were reduced over the study in a dosage-related manner. Food and water consumption by the 250 and 1000 ppm groups were decreased in a statistically significant dose-related manner over the study, and mean water consumption by the 50 ppm animals was slightly reduced but not with statistical significance. The 250 and 1000 ppm groups had a dose-related decrease in urine volume with increased osmolality, and pH was slightly reduced. Absolute kidney weights were increased in the 250 and 1000 ppm groups at the 52 and 78 week sacrifices, and decreased at 104 weeks. Relative kidney weights were increased at all sacrifice times for the 1000 ppm group, at 52 weeks for the 250 ppm group, and at 72 weeks for the 50 ppm group. The urinalysis and renal weight changes are compatible with a physiological compensatory adaptation to reduced water consumption. Gross and histological evidence for gastric irritation was observed principally in the 1000 ppm rats euthanized at 104 weeks and in animals that died during the study. Bone marrow hyperplasia and renal tubular pigmentation, seen in rats that died and the 104 week euthanasia animals, may have been secondary to a low grade hemolytic anemia in animals with large granular lymphocytic leukemia (LGLL). The only neoplasm that showed a statistically significant increase was LGLL, which occurred at a high incidence in both sexes and all groups, including the controls, for both animals that died and at the 104 week euthanasia. A few instances of LGLL were observed at 78 weeks. The overall incidence of LGLL in the spleen for the 0, 50, 250 and 1000 ppm groups was, respectively, 43, 51, 40 and 46% for males, and 24, 41, 41 and 53% for females. Statistical analyses indicated that the severity of LGLL was associated with the higher dosages of GA in female, but not male, rats. Due to the background and variable incidence of LGLL in the Fischer 344 rat, the finding of a statistical significance only for female rats, and because, there was no clear dose-response relationship, the biological significance of the LGLL findings is unclear. There is the possibility that the significance was a statistical artifact due to the low incidence of LGLL in the female control animals as a result of biological variability within the study. It is also considered to be possible that the chronic dosage of GA in the drinking water resulted in a modification of one or more of the factors responsible for the expression of this common and spontaneously occurring neoplasm in the Fischer 344 rat.

Fischer 344 (F344) F(0) weanling rats, 30/sex/group, were exposed to acrylamide in drinking water at 0.0, 0.5, 2.0, or 5.0 mg/kg/day for 10 weeks and then mated. Exposure of F(0) females continued through gestation and lactation of F(1) litters. F(0) males, after F(0) mating, were removed from exposure and mated (one male: two untreated females) for the dominant lethal (DL) assay. Thirty F(l) weanlings/sex/group were exposed for 11 weeks to the same dose levels as their parents, and then mated to produce F(2) offspring. F(0) and F(l) parents and F(1) and F(2) weanlings were necropsied. Prebreeding exposure of F(0) and F(l) animals resulted in systemic toxicity at 2.0 to 5.0 mg/kg/day, with head tilt and/or foot splay increased at 0.5 to 5.0 mg/kg/day. F(0) and F(l) reproductive indices and gestational length were unaffected. Implantations and live pups/litter at birth were reduced at 5.0 mg/kg/day. Survival of F(l) and F(2) pups was reduced at 5.0 mg/kg/day for PND 0 through 4 only. In the DL assay, total and live implants were reduced, pre- and postimplantation loss was increased, and the frequency of DL factors (F(L)%) was increased at 5.0 mg/kg/day. At 5.0 mg/kg/day, adult F(l) male peripheral nerves exhibited axonal fragmentation and/or swelling; F(l) female spinal cord sections were unremarkable. The NOEL for prenatal DL was 2.0 mg/kg/day; the NOEL for adult systemic toxicity, including neurotoxicity, was < or = 0.5 mg/kg/day. Therefore, neurotoxicity and DL were differentially affected.

Mated female CD® (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m., Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre-and postimplantation loss, sex ratio/litter, or fetal body weights/ litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD® rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.

Lung cancer continues to be a leading cause of death around the world. Staging of this disease is critically dependent upon the involvement or noninvolvement of the lymph nodes which drain the region of lung containing the lesion/tumor. Palpation, unenhanced CT, and lymph node excision (i.e., mediastinectomy) are currently used to ascertain the status of these regional draining lymph nodes. The work reported herein details the first efforts toward the pulmonary instillation of iodinated nanoparticles for contrast-enhanced CT of lung draining lymph nodes. The data reflect the impact of dose, time post instillation, and formulation (surfactant) upon the observed CT enhancement of the tracheobronchial lymph nodes of beagle dogs. In addition, initial safety is discussed with both macroscopic and microscopic observations. The results indicate that pulmonary instillation of small volumes of iodinated nanoparticles could be successfully used to aid staging of lung cancer by CT imaging.

Malformations of the maxillary incisors, diagnosed as dental dysplasia, were observed as a spontaneous background lesion in 3% (females) to 9% (males) of CD-1® mice and 14.5% (females) to 10.5% (males) of CD@ (Sprague-Dawley) rats in a chronic inhalation study. Lesions were reported grossly as overgrown, maloccluded, or malformed incisors. Microscopic findings included tooth pulp and periodontal abscesses, fractured and necrotic teeth, periodontal cysts, malformations of the incisor roots, and expansile masses, including odontomas, of the incisor roots. Development of lesions followed a pattern of tooth pulp necrosis and/or traumatic disruption of the epithelial root sheath at the base of the tooth. Feeding a powdered ration, which reduced the normal wearing of the incisors, and repeated clipping of overgrown incisors were believed to contribute to the incidence of disease.

Previous studies have indicated that ethylene glycol (EG) is a developmental toxicant in rats and mice primarily when ingested. This study was designed to establish no-observed-effect levels (NOELs) for developmental toxicity of EG administered by gavage in both rodent species. Dams were administered EG on Gestation Days 6-15; rats were given 0, 150, 500, 1000, or 2500 mg EG/kg/day; mice were dosed with 0, 50, 150, 500, or 1500 mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumption was increased during treatment and body weights were reduced throughout gestation; liver and kidney weights were increased at euthanization (Gestation Day 21). Relative liver weights were also increased at 1000 mg/kg/day. Effects observed in rat fetuses at 2500 mg/kg/day included the following: hydrocephaly; gastroschisis; umbilical hernia; fused, duplicated, or missing arches, centra, and ribs; poor ossification in thoracic and lumbar regions; and reduced body weights. Reduced body weights, duplicated or missing ribs, centra, and arches, and poor ossification were also observed in rat fetuses at 1000 mg/kg/day. In mice, there was no apparent treatment-related maternal toxicity. In mouse fetuses (Gestation Day 18), effects were observed at 1500 mg/kg/day and included reduced body weights, fused ribs and arches, poor ossification in thoracic and lumbar centra, and increased occurrence of an extra 14th rib. At 500 mg/kg/day, slight reductions in fetal body weight and increased incidences of extra ribs were observed. Under conditions of these studies, NOELs for developmental toxicity were 500 mg/kg/day for rats and 150 mg/kg/day for mice, indicating that mice were more susceptible than rats to the teratogenic effects of EG.

A 6-year-old crossbreed dog had recurring nodular masses on the dorsum of the head which were diagnosed as multilobular osteosarcoma. At necropsy, metastases were present throughout the lungs. Histological features of the masses included multiple islands of cartilage and bone separated by a dense fibrovascular stroma. These tumours are slow growing malignant neoplasms which may metastasize.

Four groups, each consisting of 10 male and 10 female Fischer-344 rats, were exposed 6 h/day, 5 days/week, for 9 days to diisobutyl ketone (DIBK) vapor at concentrations of 905, 300, 98, or 0 (con trol) ppm. An additional 10 rats/sex were assigned to the 905 and 0 ppm groups and allowed two weeks recovery prior to sacrifice. Rats exposed to 905 ppm had mild ocular irritation (lacrimation) and evidence of kidney toxicity, manifested as: 1) an increase in absolute and relative (as a percentage of body weight) kidney weights, 2) an increase in urine volume (and water intake) with a concomitant decrease in urine osmolality (males only), and 3) an increase in severity of hyalin droplet nephrosis in the proximal tubules (males only). Absolute and relative liver weights were also increased in both male and female rats of the 905 and 300 ppm groups. These effects either disappeared or lessened in severity fol lowing the 2-week recovery period. Male rats exposed to 300 ppm had similar renal alterations to the males of the 905 ppm group, although the alterations were fewer in number and smaller in mag nitude. Kidney weights and renal histology of the males of the 98 ppm group were similar to the control male rats, although an increase in urine volume with a decrease in urine osmolality was observed. The kidney findings in this study were not surprising because of the chemical relationship of DIBK with other aliphatic ketones (e.g., methyl isobutyl ketone, methyl isoamyl ketone) which, after repeated inhalation exposure, cause hyalin droplet nephropathy in male rats. The significance of this male rat nephro sis with regard to human exposure is unknown.

Male C3H/HeJ mice were thrice weekly given 25 microliter applications of 0.25, 0.05, or 0.01% (w/w) benzo(a)pyrene (BaP) in acetone, or acetone alone, to clipped dorsal skin from 12 to 14 weeks of age for the remainder of their life spans. There were two groups of 40 mice for each treatment regimen, one group being housed in conventional stainless-steel wire mesh cages and the other in polycarbonate cages with wood shavings held in an enclosed ventilated cabinet. Under both housing conditions, tumor incidence was directly related and latency inversely related to BaP concentration. The time-adjusted incidence of epidermal neoplasms was significantly greater for the groups housed in polycarbonate cages. Mortality rates were directly related to BaP concentration and were significantly enhanced by the polycarbonate-cage housing conditions for the high and intermediate concentrations. Survival patterns for the two acetone control groups were similar. These findings indicate that differences in housing conditions can influence both the incidence and the latency of local neoplasms produced in response to the chronic application of a carcinogen in dermal oncogenesis bioassays.

Inhalation of aerosols of the ethylene oxide/propylene oxide polymer (U-5100) evaluated in this study has previously been shown in acute and 2-week studies to produce toxicologic effects on the lungs, with increased lung weights and microscopic findings of congestion and hemorrhage of pulmonary alveolar capillaries and necrosis of alveolar epithelial cells D. R. Klonne, D. J. Nachreiner, D. E. Dodd, P. E. Losco, and T. R. Tyler 1987, Fundam. Appl. Toxicol. , 9 , 773–784). In the present studies, F-344 rats were exposed 6 hr/day, 5 day/week for 2 weeks to aerosols at mean concentrations of 0, 0.9, or 5.0 mg/m 3 or for 13 weeks to mean concentrations of 0, 0.3, 1.1, or 5.2 mg/m 3 . Following the 2-week study, minimal multifocal hemorrhage and eosinophilic proteinaceous debris in alveoli were observed in the 0.9 mg/m 3 group; similar lesions plus alveolar cell necrosis were found in the 5 mg/m 3 group. In the 13-week study, the 5.2 mg/m 3 group had a slight decrease in body weight gain, while increases in absolute and/or relative lung weights occurred for both the 1.1 and 5.2 mg/m 3 groups at the end of the exposure regimen and at the end of a 5-week recovery period. Histologic lesions of the lungs occurred in all U-5100-exposed groups and consisted of hemorrhage, alveolar histiocytosis, interstitial pneumonia, and multifocal fibrosis. The incidence and severity of the pulmonary lesions were concentration related. At the end of the 5-week recovery period, there was little change in the severity or incidence of the pulmonary lesions in the 1 and 5 mg/m 3 groups when compared to rats killed the day after the termination of exposures. In conclusion, exposure to aerosols of U-5100 for 13 weeks produced generally slight but biologically significant pulmonary fibrosis in rats at all the exposure concentrations tested in this study.