In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.

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Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats.

To analyze the implications for human health, the toxicologist requires four sets of data: the results of toxicity and other studies in animals; quantitative data on actual or potential human exposure; whatever information is available on effects of exposure in man; and the statistical extrapolations from the dose-response relationships in animals to the (usually) much lower levels of human exposure. Professional expertise in toxicology is essential to assess the nature and severity of the toxic effects observed in animals, including such characteristics as potential for progression, irreversibility and production of incapacity. Given sufficient data, an estimate can be arrived at of the likelihood that such effects will be elicited in human populations of differing susceptibilities. The criteria by which the overall implications for human health can be judged comprise both the direct effects on man, as well as the indirect consequences stemming from environmental impacts.

Implications for human health.

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.

https://journals.sagepub.com/doi/pdf/10.1080/10915810290096306

Evaluation of the Carcinogenic Potential of Insulin Glargine (LANTUS) in Rats and Mice

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 soft tissues including skeletal muscle as well as the mesothelium of rats and mice. The standardized nomenclature of 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 lesions in soft tissues, skeletal muscle and mesothelium 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. (DOI: 10.1293/tox.26.1S; J Toxicol Pathol 2013; 26: 1S-26S).

Proliferative and Non-Proliferative Lesions of the Rat and Mouse Soft Tissue,Skeletal Muscle and Mesothelium

The definition of mitogenic activity of insulin is controversial. Under physiological conditions, mitogenic refers to cell proliferation and tissue repair. In pathological conditions, it may refer to stimulation of tumour cells in pre-existing (undiagnosed) tumours. The in vitro investigations using benign and malignant cell lines compare proliferative activity of insulin molecules (animal, human and analogues). In these studies, inclusion of [B10-Asp] insulin would be a valuable link to the existing evidence on proliferation of mammary tissue in rodents. Animal and human insulin have growth promoting activity on spontaneously arising tumours (e.g. mammary tumours in rodents). They have no carcinogenic activity (cell transformation), and moreover insulin is not a co-carcinogen when evaluated in special toxicology. Mitogenicity (growth promoting activity) of insulin may be a problem in people with undiagnosed tumours, and may require definition of patient groups who would benefit from targeted monitoring.

L Goldberg

Papers

Subcutaneous Sarcoma as an Index of Carcinogenic Potency