Proliferative and nonproliferative lesions of the rat and mouse urinary system.

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 lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the urinary tract of rats and mice. The standardized nomenclature of urinary tract lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for urinary tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice.

Insulin glargine (LANTUS) is a new, long-acting insulin analogue with a stable profile of action. The purpose of these studies was to evaluate the carcinogenic potential of insulin glargine in rats and mice. General toxicity studies were conducted in NMRI mice (3 months' duration) and rats (Wistar rats in the 3- and 6-month studies and Sprague-Dawley rats in the 12-month study) to determine the optimal dose of insulin glargine for long-term carcinogenicity studies. Based on these results, groups of Sprague-Dawley rats or NMRI mice (50 male, 50 female) received a daily subcutaneous dose of 2, 5, or 12.5 IU/kg of insulin glargine or 12.5 (mice) or 5 IU/kg (rats) of the reference insulin (NPH insulin) in a lifetime study. Similarly treated control and vehicle-control animals received isotonic sodium chloride (NaCl) solution or the vehicle solution, respectively. In mice, the mortality rate was comparable between all groups. In rats, the mortality rate compared with the NaCl control was significantly increased in the following groups: males treated with the vehicle control, all insulin glargine and NPH insulin groups, and in females in the high-dose insulin glargine and NPH insulin groups. There was no difference in the incidence of mammary tumors reported in both mice and rats when comparing the insulin glargine groups with the NaCl, vehicle-control, or the NPH insulin groups. In rats and mice, the distribution of subcutaneous malignant fibrous histiocytomas found at the injection site were not dose-dependent. These lesions are a rodent-specific event and were related to chronic tissue irritation and inflammation. In rats, neuronal necrosis of the cerebrum was attributed to persistent repeated episodes of hypoglycemia induced by high doses of insulin. In these studies, there were no neoplastic findings to indicate that insulin glargine had a systemic carcinogenic potential in mice or rats.