Search

The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague–Dawley (Crl:CD®(SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague–Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene ( Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3–13) of the Bhd gene was sequenced, and a guanine (nt106G) to adenine (nt106A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms.

Neoplasms of preputial gland and skin were obtained from Fischer 344 male rats on lifetime drinking water studies of the benzidine congener 3,3′-dimethoxybenzidine, C.I. Direct Blue 15 or C.I. Acid Red 114, bisazobiphenyl dyes derived from 3,3′-dimethoxybenzidine and 3,3′-dimethylbenzidine. Portions of these well differentiated neoplasms were implanted into the left mammary fat pad of Fischer 344 male recipients. The rate of growth, presence of local invasion and distant metastases, and morphologic features were observed following 4 serial transplantations. All implants appeared early, grew rapidly, and were histomorphologically similar to the original neoplasms. Metastases from transplants were observed with both preputial gland and skin tumor lines in serial passages. The transplantation results confirm the malignant nature of these neoplasms.

The effect of butylated hydroxytoluene (BHT) and diphenyl-p-phenylenediamine (DPPD) on cancer induction by N-2-fluorenylacetamide (FAA) and its N-hydroxy derivative (N-OH-FAA) has been studied in two strains of rat. Groups of Charles River rats were fed carcinogen and antioxidant in a molar ratio of 1:30 (223 ppm FAA or 239 ppm N-OH-FAA (1 mM) and 7850 ppm DPPD or 6600 ppm BHT) in Wayne Chow for 24 wk (males) or 32 wk (females). Male and female rats then continued on control diet for another 12 wk. With FAA alone 70% of male rats had hepatoma and 20% of females had mammary adenocarcinoma; with N-OH-FAA, 60% of males had hepatoma and 70% of females had mammary adenocarcinoma. The simultaneous administration of DPPD failed to alter cancer induction by these agents in male or female rats. However, BHT reduced the incidence of hepatoma in males to 20% when the carcinogen was FAA. With N-OH-FAA, BHT lowered the incidence of liver tumours to 15% and of mammary cancer in females to 35%. Similar data on inhibition by BHT were obtained using different levels of carcinogens in rats of the Fischer strain. Equimolar levels of sulphate failed to increase liver-tumour incidence in animals given N-OH-FAA and BHT. Also, BHT failed to depress the excretion of free urinary inorganic sulphate. Liver- and oesophageal-tumour induction with 51 ppm diethylnitrosamine in drinking water for 24 wk was not affected by BHT or DPPD, nor was tumour induction by propane sultone.

The benzidine congener 3,3′-dimethoxybenzidine (DMOB), and C.I. Direct Blue 15 (Blue 15), a prototypical compound of the DMOB-derived class of dyes, were evaluated in 13-week studies to characterize the toxicity and establish dose levels for subsequent chronic studies. Groups of 10 Fischer 344 rats of each sex were administered either DMOB, or Blue 15, at 1 of 5 concentrations in drinking water for 13 weeks. DMOB concentrations were 0, 0.017, 0.033, 0.063, 0.125, and 0.25% for males and females. For Blue 15, the concentrations were 0.063, 0.125, 0.25, 0.50, and 1.0% for females and 0, 0.125, 0.25, 0.50, 1.0, and 3.0% for male rats. Rats showed dose-related decreases in water consumption and weight gains. All DMOB-treated rats and their controls survived the 13-week treatment. There were 7 deaths in the 3% level of male rats treated with Blue 15. Liver and kidney weights were increased in rats treated with both compounds. Target organs for DMOB-treated rats were the kidney and thyroid. These lesions were characterized by chronic nephropathy, and increased pigment in the follicular cells of the thyroid. The kidney and liver were identified as target organs for Blue 15-treated rats. In the high-dose rats that died before termination of the study, renal effects were characterized by degeneration and focal necrosis of proximal tubular epithelial cells. Liver lesions in this group consisted of degeneration and necrosis of hepatocytes, fatty metamorphosis, and minimal megalocytosis. Mild chronic nephropathy was the principal histological effect in Blue 15-treated rats surviving to study termination.

Feeding 1,4-bis(fluorophenyl)-2-propynyl-N-cyclooctyl carbamate to F344 or Sprague-Dawley male rats at 125-500 ppm in the diet led to many carcinomas of the small intestine and ear duct (Zymbal's gland tumors) in addition to lymphomas and leukemias. A high incidence of mammary adenocarcinomas was found in the Sprague-Dawley rats. Only a few colon or liver tumors were observed in each strain.