Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse.

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 Japan (JSTP), Europe (ESTP), Great Britain (BSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The primary purpose of this publication is to provide a standardized nomenclature for characterizing lesions observed in the cardiovascular (CV) system of rats and mice commonly used in drug or chemical safety assessment. The standardized nomenclature presented in this document is also available electronically for society members on the internet (http://goreni.org). Accurate and precise morphologic descriptions of changes in the CV system are important for understanding the mechanisms and pathogenesis of those changes, differentiation of natural and induced injuries and their ultimate functional consequence. Challenges in nomenclature are associated with lesions or pathologic processes that may present as a temporal or pathogenic spectrum or when natural and induced injuries share indistinguishable features. Specific nomenclature recommendations are offered to provide a consistent approach.

Proceedings of the 2010 National Toxicology Program Satellite Symposium.

The 2010 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held in Chicago, Illinois, in advance of the scientific symposium sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The goal of the annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for voting or discussion. Some topics covered during the symposium included a comparison of rat and mouse hepatocholangiocarcinoma, a comparison of cholangiofibrosis and cholangiocarcinoma in rats, a mixed pancreatic neoplasm with acinar and islet cell components, an unusual preputial gland tumor, renal hyaline glomerulopathy in rats and mice, eosinophilic substance in the nasal septum of mice, INHAND nomenclature for proliferative and nonproliferative lesions of the CNS/PNS, retinal gliosis in a rat, fibroadnexal hamartoma in rats, intramural plaque in a mouse, a treatment-related chloracne-like lesion in mice, and an overview of mouse ovarian tumors.

Time management for preclinical safety professionals.

A survey about time management in the workplace was distributed to obtain a sense of the level of job satisfaction among preclinical safety professionals in the current economic climate, and to encourage reflection upon how we manage time in our work environment. Roughly equal numbers of respondents (approximately 32%) identified themselves as management or staff, and approximately 27% indicated that they are consultants. Though 45.2% of respondents indicated that time management is very challenging for the profession in general, only 36.7% find it very challenging for themselves. Ten percent of respondents view time management to be exceedingly challenging for themselves. Approximately 34% of respondents indicated that prioritization of tasks was the most challenging aspect of time management for them. Focusing on an individual task was the second most challenging aspect (26%), followed equally by procrastination and delegation of tasks (12.4%). Almost equal numbers of respondents said that they would (35.2%) or might (33.3%) undertake training to improve their time management skills. Almost equal numbers of participants responded "perhaps" (44.6%) or "yes" (44.2%) to the question of whether management personnel should be trained in time management.

Histomorphology and vascular lesions in dorsal rat skin used as injection sites for a subcutaneous toxicity study.

Subcutaneous injection of pharmaceutical compounds into the dorsal skin of rats is common in preclinical and nonclinical studies. However, no detailed histologic description of this anatomic location has been published to date. Following the observation of vascular lesions in the dorsum of rats in a thirteen-week toxicity study, a complementary study was performed on untreated Sprague-Dawley rats to evaluate the normal histology of the skin and subcutis, the potential effect of chronic subcutaneous injection on the morphology of the skin and its vasculature, and the spontaneous vascular pathology in the areas used as injection sites in the principal study. This study showed that saline injection did not fundamentally alter the morphology of the injection sites used for the principal study. Skin thickness was greater in males than in females. Although acellular intimal thickening occurred spontaneously in the dorsal skin of untreated males and females, only males had a spontaneous incidence of intimal hyperplasia. No site predilection for intimal lesions was apparent for either sex. Saline injection, or the physical trauma of injection, may induce intimal hyperplasia; males appear more likely to develop the lesion than do females. It is possible that acellular intimal thickening can progress to intimal hyperplasia under appropriate conditions.

Performance of the Ascensia ENTRUST glucose meter for determination of blood glucose concentration in rats.

BACKGROUND: The Ascensia ENTRUST blood glucose meter is intended for self-monitoring of blood glucose by diabetic patients. Use of such a glucometer would minimize blood volume requirements for the measurement of glucose in small laboratory animals. OBJECTIVE: The purpose of this study was to assess the performance of the Ascensia ENTRUST for measuring glucose in whole blood from Wistar rats by evaluating the effect of anticoagulant and sample processing delay and comparing normalized results with plasma glucose concentration. METHODS: Blood samples were collected from the retroorbital sinus of 30 male Wistar rats with a wide range of blood glucose concentrations. Glucose concentration was measured with the Ascensia ENTRUST in nonheparinized (NH) and heparinized samples immediately after collection (Hep-0) and in heparinized samples after a 15 min delay at 23-28 degrees C (Hep-15). Heparinized samples were centrifuged and glucose concentration was determined in plasma using an automated chemistry analyzer. Results were compared to assess the effect of anticoagulant (NH vs Hep-0) and time (Hep 0 vs Hep 15), and to compare normalized Hep-15 results with plasma glucose concentration. RESULTS: Glucose concentration was not significantly different between NH and Hep-0 samples. Glucose concentration was lower in Hep-15 (77+/-36.9 mg/dL) than Hep-0 (88+/-39.7 mg/dL) samples, but the difference was not significant. With normalization, Hep-15 glucose concentration correlated well (r>or=.98) with plasma glucose concentration but was lower by 6.0+/-16.7 mg/dL, with a positive bias at low glucose concentrations and a negative bias at high concentrations. CONCLUSION: The Ascensia ENTRUST may be adequate for repeated blood glucose measurements in rats, but its results do not accurately predict plasma glucose concentrations measured by an automated clinical chemistry analyzer.

Intimal hyperplasia in rats after subcutaneous injection of a somatostatin analog.

The somatostatin analog octreotide was administered to male and female Sprague-Dawley rats by subcutaneous injection for thirteen weeks at 0 (saline control), 0 (placebo control [mannitol and lactic acid; pH 4.2]), 1.25 mg/kg/day and 2.5 mg/kg/day to explore its potential effect on cutaneous vascular morphology. The placebo caused an increase in the incidence of intimal hyperplasia compared to saline controls in female rats; octreotide increased the incidence and severity of intimal hyperplasia in males and females. Intimal hyperplasia consisted of increased numbers of cells located between the endothelial cell layer and the internal elastic lamina. Severity was based on the degree of compromise of the vascular lumen (regardless of vessel size and number), with severely affected vessels having no visible lumen. Intimal hyperplasia in rats treated with octreotide was considered to be an unexpected and adverse finding, given that this compound and other somatostatin analogs have been investigated as reducers of intimal proliferation or restenosis after angioplasty in humans and that no such lesion has been reported in the literature for this class of compound to date. The induction of intimal hyperplasia by the placebo is also a notable finding; this may be because of the low pH of the formulation.

The transgenic mouse assay as an alternative test method for regulatory carcinogenicity studies--implications for REACH.

REACH, an EU regulation that requires the submission of safety data in support of the protection of human and environmental health, mandates that registration should be achieved with the minimum amount of animal testing possible. Under REACH, a two-year carcinogenicity assay may be required for certain chemicals produced at >1000 metric tonnes per year. In addition, some chemicals that are found to be genotoxic will also require testing. Alternative methods have been explored in an attempt to improve the predictivity of this bioassay as well as to reduce the number of animals used for such testing. This research has focused on the use of transgenic/knockout mouse models. Study results from selected models indicate that they are useful in hazard identification, even if they are not entirely suitable for risk assessment on their own. Carcinogenic hazard assessment can be greatly enhanced and animal use reduced if the traditional two-year rat bioassay is combined with a well conducted transgenic mouse assay. Importantly, the use of transgenic animals to supplement a traditional two-year carcinogenicity study may help reduce the number of false negatives, one of the unstated goals of REACH via the precautionary principle.

Cerebral vacuolation induced in rats by the administration of LUP-3FDC, an anti-tuberculosis cocktail.

A study was conducted to determine the subacute oral toxicity of LUP-3FDC (a cocktail composed of rifampicin, isoniazid and pyrazinamide) and LUP-Q1 (gatifloxicin sesquihydrate) as well as the potential effects of their combination when administered as repeated sublethal oral (gavage) doses for a period of 90 days in seven (7) groups of Wistar rats. Three (3) additional groups were allowed to live for 28 days after the end of treatment to evaluate the potential reversibility of any toxic effects observed. Mortality was observed at all dose levels. General body weakness and hind limb paralysis (attributable to peripheral neuropathy) were observed in animals administered 1400mg/kg/day LUP-3FDC, 800mg/kg/day LUP 3-FDC+300mg/kg/day LUP Q1 and 1400mg/kg/day LUP-3FDC+300mg/kg/day LUP-Q1. The administration of LUP-3FDC at doses of 1100 or 1400mg/kg/day or a combination of 1400mg/kg/day LUP-3FDC and 300mg/kg/day LUP-Q1 induced an increased incidence of vacuolation in the brain compared to control animals. This effect, which was observed predominantly in the cerebellar roof nuclei, was attributed to the isoniazid component of the compound. Vacuoles were located primarily in the myelinated areas close to cerebellar roof nuclei, but were also seen in the olfactory tubercle, thalamus, cerebral cortex, septum and basal ganglia. Females were more susceptible to this change; vacuoles were still evident in males and females 28 days after the cessation of compound administration. The rat cerebellum is prone to develop vacuolation with age; isoniazid may "accelerate" or "enhance" this tendency in young rats.