A large subcutaneous mass was observed at necropsy in the right neck area of a 95-week-old female Fischer 344 rat that served as an untreated control animal in a 2-year carcinogenicity study. Formalin-fixed, paraffin-embedded sections of the mass were stained with hematoxylin and eosin along with the immunohistochemical biomarkers lactoperoxidase, catalase, and amylase. Based on its histomorphological and immunohistochemical features, the lesion was diagnosed as a carcinoma of the extraorbital lacrimal gland.

Two-week and 13-week studies were conducted to determine the toxicity of lactide when the compound is administered orally in gelatin capsules to beagle dogs. In the 2-week study, daily doses of 0, 10, 100, 400, 1000 and 2500 mg/kg body weight/day were administered to dogs of both sexes for 14 consecutive days. All dogs survived to the end of the study. Clinical signs consistent with irritation of the alimentary tract occurred in dogs in the 1000 and 2500 mg/kg dose groups. Reductions in body weight gain and in absolute and relative thymus weights were observed in the same two dose groups, and reductions in absolute and relative spleen weights were seen in the 2500 mg/kg dose group. These changes were considered to be secondary to the stress resulting from irritation of the gastrointestinal tract. Gross and microscopic lesions were indicative of irritation, and included dark foci and haemorrhage of the stomach lining, and erosion and ulceration of the stomach and the oesophagus. Also noted in all high-dose dogs was renal tubular regeneration, which may represent repair of previous necrosis of the tubular epithelium. In the 13-week study, no deaths occurred when dogs were given daily oral doses of 0, 4, 20 or 100 mg/kg body weight/day. No clinical signs of toxicity were observed, and the compound had no effect on body weights, food consumption, or any of the clinical chemistry, haematology or urinalysis parameters assessed. Gross and microscopic findings considered to be potentially related to lactide administration were minimal, and included a stomach focus in one dog of each sex in the 100 mg/kg group. The stomach focus in the 100 mg/kg female dog was manifested microscopically as a stomach ulcer. Based on these results, the primary toxic effect of lactide was considered to be irritation of the gastrointestinal tract, and the no-observed-adverse-effect level (NOAEL) after subchronic oral dosing in dogs was considered to be 100 mg/kg/day.

An enlarged pineal gland was observed in a 112-wk-old male Fischer 344 rat from the low-dose treatment group in a 2-yr bioassay. Formalin-fixed, paraffin-embedded sections of the gland were stained with hematoxylin and eosin along with the immunohistochemical biomarkers synaptophysin, placental alkaline phosphatase, glial fibrillary acidic protein, and vimentin. Based on its histomorphological features and on positive staining with synaptophysin, the lesion was diagnosed as a malignant pineal gland parenchymal cell tumor or pineocytoma of incidental origin.

Combination therapy with anti-HIV drugs and opportunistic infection drugs is a common practice in treatment of AIDS patients. Although toxic effects of most individual therapies are known, the toxic potential of most combination therapies has not been established. To understand the toxic consequences of combination therapies, the commonly used anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) and tuberculosis infection therapies pyrazinamide, isoniazid, and rifampicin were evaluated by 13-week gavage studies in B6C3F1 mice, either alone or AZT in combination with one of the antituberculosis drugs. The doses include AZT 100, 200, and 400; pyrazinamide 1000 and 1500; isoniazid 50, 100, and 150; and rifampicin 100, 200, and 400 mg/kg/day, AZT alone caused hematopoietic toxicity with dose-related bone marrow suppression, macrocytic anemia, and thrombocytosis. Pyrazinamide or isoniazid alone at the doses tested did not cause significant toxicity. Rifampicin alone caused hematopoietic toxicity and possibly mild hepatic toxicity. Pyrazinamide below 10 times the therapeutic dose when given with AZT did not increase the hematological toxicity of AZT, Isoniazid markedly increased the hematological toxicity of AZT and contributed to mortality at 3 to 4 times the therapeutic dose combinations. Administration of rifampicin with AZT at the calculated therapeutic doses resulted in toxicity of far greater magnitude than that caused by AZT or rifampicin alone. Combination treatment with AZT and rifampicin caused severe anemia with mortality at 2 to 4 times the therapeutic dose combinations. However, AZT did not enhance the hepatotoxicity of rifampicin. Increased hematopoietic toxicity of AZT when given in combination with the above antituberculosis drugs may be due to changes in the metabolism of AZT, Results of these studies indicate that toxicological effects of combination therapies could be considerably more severe than and different from the toxicity of individual therapies,

2',3'-dideoxycytidine (ddC) is a synthetic pyrimidine nucleoside analogue approved for treatment of HIV-positive patients. Previous studies indicated that ddC has the potential to cause thymic lymphoma in C57BL/6 x C3H F1 (hereafter called B6C3F1) mice. In this study, we evaluated the carcinogenic potential of ddC in two different mouse models. B6C3F1 hybrid mice carry ecotropic endogenous proviral sequences that may be activated to cause lymphoma, whereas NIH Swiss mice lack proviral sequences that can be expressed. The mice were treated with ddC by gavage at 500 and 1000 mg/kg/day for up to 6 months (human dose, 2.25 mg/day) and evaluated for toxicity, plasma levels of ddC, and pathological changes. Lymphocyte cell markers from the thymic lymphomas were assessed by immunophenotyping. Expression of p53 protein was evaluated using immunohistochemical staining. Treatment-related thymic lymphomas were present in both mouse models with a higher incidence in NIH Swiss than in B6C3F1 mice. The lymphomas were more prevalent in females than in males of both mouse models. Most mice with thymic lymphoma died during the course of the study. In addition to the thymus, lymphoma was often present in lymph nodes, spleen, and other organs. Lymphomas arose more frequently in mice that lack endogenous ecotropic retroviral sequences and thus were not due to activation of endogenous provirus. During the third month of the study, a few NIH Swiss mice that died had granulosa cell tumors of the ovary. Treatment-related but reversible thymic atrophy was observed in both mouse models. There was a very high correlation between the internal dose of ddC and the incidence of thymic lymphoma in both mouse models. Most of the lymphocytes from control thymuses and ddC-induced lymphomas were positive for Thy-1.2 (pan-T), heat stable antigen, and CD4 and CD8 markers, with no marked differences in the lymphocyte markers of the tumors between sexes or dose groups. p53 protein was detected in only 20% (23/115) of the ddC-induced lymphomas with mostly minimal expression in scattered cells. Because ddC induced lymphomas in two different mouse models, the potential carcinogenic risk should be considered in long-term treatment of HIV-positive patients, especially children and adolescent patients treated with ddC.