Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2; greater than 99.7% pure) were conducted in groups of 60 F344/N rats and 60 B6C3FW mice of each sex for each of three exposure doses and vehicle controls. These composite studies on benzene were designed and conducted because of large production volume and widespread human exposure, because of the epidemiologic association with leukemia, and because previ. ous experiments were considered inadequate or inconclusive for determining carcinogenicity in laboratory animals. Using the results from 17-week studies, doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten animals in each of the 16 groups were killed at 12 months, and necropsies were performed. Hematologic profiles were performed at 3-month intervals.For the 2-year studies, mean body weights of the top dose groups of male rats and of both sexes of mice were lower than those of the controls. Survivals of the top dose group of rats and mice of each sex were reduced; however, at week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, Harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene in male F344/N rats, female F344/N rats, male B6C3FW mice, and female B6C3FM mice. In male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. In female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity. In male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. In female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and careinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcin...
Groups of 80 male and female F344 rats were exposed by gavage to ochratoxin A, a naturally occurring mycotoxin, at levels of 21, 70, and 210 micrograms/kg body weight for up to 2 years. Ochratoxin A induced non-neoplastic renal tubular epithelial changes consisting of cytoplasmic alteration, karyomegaly, degeneration, and cysts. Exposure-related renal tubular proliferative lesions included focal hyperplasia, tubular cell adenoma, and tubular cell carcinoma. Renal tubular cell adenoma occurred as early as 9 months in 1 high-dose male rat, and both adenomas and carcinomas were seen in males by 15 months. At the terminal sacrifice, renal tubular cell tumors were found in both male and female rats, but the response was more pronounced in the males. The incidence of renal tumors in the high-dose rats was the highest of any National Toxicology Program (NTP) study completed to date. In the high-dose males approximately one-third of the renal carcinomas developed metastases. This study demonstrates that ochratoxin A is a potent renal carcinogen in the F344 rat and suggests that contamination of feedstuff by this mycotoxin may pose a potential hazard to domestic animals and man.
Male and female F-344 rats and B6C3F1 mice (10/sex/group) were exposed to N,N-dimethylformamide (DMF) by whole body inhalation exposure at 0, 50, 100, 200, 400, or 800 ppm, 6 h/day, 5 days/week, for 13 weeks. A concentration-dependent depression in body weight occurred in rats of both sexes at 400 (6-11%) and 800 ppm (20-22%). In contrast, all weight changes in both sexes of mice were within 10% of controls. No rats died, while 5 mice died from nonexposure-related causes. Relative liver weights were significantly increased at all DMF concentrations in both sexes and both species. Activities of serum sorbitol dehydrogenase (SDH) were statistically increased in male and female rats (200 to 800 ppm) on study days 4, 24, and 91 (13 weeks). Activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICD) were statistically increased in both sexes of rats exposed to 800 ppm DMF at all time points. Cholesterol (CHOL) levels were statistically increased in male and female rats (50-800 ppm) at all sampling time points. Levels of total bile acids (TBA) were statistically increased in both sexes of rats (400-800 ppm) on days 24 and 91. Centrilobular hepatocellular necrosis (minimal to moderate) was seen in rats of both sexes exposed at 400 and 800 ppm, with the lesions more severe in females. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of DMF-exposed male mice, and in female mice exposed at 100-800 ppm. For male and female rats the no-observed-adverse-effect concentration (NOAEC) for microscopic liver injury was 200 ppm. The NOAEC was 50 ppm for female mice, but an NOAEC based upon the absence of microscopic liver injury was not determined in male mice.
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