A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats.

This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization. Rats were observed for viability, clinical signs of toxicity, and changes in body weight and food consumption. At necropsy, selected organs were weighed, macroscopic observations were recorded, and tissues were collected, fixed, processed, and examined for microscopic pathologic findings. Acute quinacrine toxicity was evident during the dosing period but did not affect long-term survival. Non-neoplastic findings were more common in treated animals than controls, providing evidence of the appropriateness of the bioassay. The incidence of uncommon tumors of the reproductive tract was similar to controls at doses of 10/10mg/kg but increased with dose level and was significantly greater than controls at >or=70/70 mg/kg. We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at a local dose approximately 8 times the human dose used for non-surgical female sterilization increased the lifetime risk of tumor development in the reproductive tract.

Development of hibernomas in rats dosed with phentolamine mesylate during the 24-month carcinogenicity study.

Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora cavernosa. Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets. This study documents the previously unreported development of hibernomas in rats treated with phentolamine mesylate.

An evaluation of changes and recovery in the olfactory epithelium in mice after inhalation exposure to methylethylketoxime.

Methylethylketoxime, also known as MEKO or 2-butanone oxime (CAS No. 96-29-7), is a clear, colorless to light yellow liquid at room temperature. It is an industrial antioxidant used as an antiskinning agent in alkyd paint, an industrial blocking agent for urethane polymers, and a corrosion inhibitor in industrial boilers, and can be found in some adhesives and silicone caulking products. Male CD-1 mice were exposed 6 h/day, 5 days/wk, for 1, 2, 4, or 13 wk via whole-body inhalation exposures to MEKO vapor concentrations of 0, 3 +/- 0.1, 10 +/- 0.3, 30 +/- 1, or 100 +/- 2 ppm (10 mice/group/interval). Satellite animals were removed after 1, 2, 4, or 13 wk of exposure and allowed to recover for 4 or 13 wk (5 mice/group/interval). After termination, the nasal turbinates were evaluated microscopically, and cross-sectional nasal maps of the lesions were prepared. At the end of the 1-, 2-, 4-, and 13-wk exposure periods, degeneration of the olfactory epithelium lining the dorsal meatus was seen in the anterior region of the nasal cavity. In a few instances, the olfactory epithelium covering the tips of the nasoturbinal scrolls projecting into the dorsal region of the nasal cavity was also degenerated. Large areas of olfactory epithelium lying laterally and posteriorly were unaffected. In general, approximately 10% or less of the total olfactory tissue was affected. In several instances, the degenerated olfactory epithelium was reepithelialized by squamous/squamoid and/or respiratory types of epithelium. Degeneration, which was dose related in incidence and severity, was seen in mice exposed to 30 and 100 ppm after 1 wk of exposure and in several mice exposed to 10 ppm after 13 wk of exposure. The incidence and severity of the degeneration present after 1 wk of exposure did not increase with the longer exposures. The olfactory degeneration was reversible. Recovery was complete within 4 wk following exposures at 10 ppm and nearly complete within 13 wk after exposures at 30 and 100 ppm. A no-observed-effect level (NOEL) for the olfactory degeneration was considered to be 3 ppm.