Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice.

Abstract

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...

Mechanisms of Multistep Carcinogenesis and Carcinogen Risk Assessment

“…The data supporting the conclusion that DES and asbestos are chromosome mutagens have already been discussed. Benzene, a known human carcinogen, has been reported as negative in most gene mutation assays, but some positive results have been presented (95)(96)(97). However, clear evidence exists that cytogenetic damage is induced by benzene (63), indicating that it is primarily an inducer of chromosome damage, and this is likely its major mechanism ofaction.…”

Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma

“…Benzene induces NHL in experimental studies of mice and rats (Farris et al 1993, Huff et al 1989. Occupational studies of solvent exposures suggest that initiation of NHL is the result of DNA damage and subsequent defects in DNA repair systems (Zhang et al 2007, Tompa et al 1994, Biro et al 2002.…”

Frequent p53 and H-ras Mutations in Benzene- and Ethylene Oxide-Induced Mammary Gland Carcinomas from B6C3F1 Mice

“…Both benzene and EtO induce mammary carcinomas in female B6C3F1 mice (NTP, 1986(NTP, , 1987Huff et al, 1989) (Table 1). These chemically induced mammary neoplasms exhibited a variety of histologic patterns, although no specific pattern was associated with a particular chemical or dose group.…”

“…Benzene is a well-documented environmental pollutant that induces hematotoxicity and hematopoietic neoplasia in humans (IARC, 1994;NTP, 2004) and is a multisite carcinogen in rodents, including the development of mammary carcinomas in mice (Maltoni and Scarnato, 1979;Huff et al, 1989;Maltoni et al, 1989;NTP, 2004). Several studies indicate that metabolism of benzene to its reactive metabolites is a prerequisite for its cytotoxic, genotoxic, and carcinogenic properties (Gut et al, 1996;Snyder and Hedli, 1996;Valentine et al, 1996;Abernethy et al, 2004).…”