(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

mammary gland (female), and skin (male). In the mouse, Zymbal gland, lung, Hardarian gland
(male), preputial gland (female), mammary gland (female), and ovary tumors are produced.
Thus, the target organs for carcinogenesis differ between rodents and humans.
In several inhalation studies, one or a few examples of bone marrow malignancies in mice were
found (Snyder et al., 1980; Goldstein et al., 1982). The findings were not statistically significant
but were unusual, in that spontaneous occurrences of these tumors had not been reported
previously. Cronkite et al. (1989) produced thymic lymphoma in 6 of 90 C57Bl/6 mice exposed
to 300 ppm benzene. In this study, exposure was for 16 weeks, with clinical observations until
death. However, the C57Bl/6 strain does have a background level of spontaneous leukemia.
Cronkite et al. (1989) later showed that CBA/Ca mice exposed to 300 ppm benzene for 16
weeks developed an increased incidence of myelogenous neoplasms. However, in an attempt
to study this event further, Farris et al. (1993) were unable to reproduce the effect seen by
Cronkite et al. (1989) in the CBA/Ca mouse, but did find malignant lymphoma and preputial
gland carcinoma, Zymbal gland carcinoma, and squamous cell carcinoma in the forestomach.
Except for the study conducted by Goldstein et al. (1982), other studies (prior to the work of
French and Saulnier [2000]) have failed to produce AML in rodents via benzene exposure.
Thus, while the hematopoietic abnormalities associated with benzene exposure are
reproducible in test animals, leukemogenic effects are generally not observed, and therefore,
the animal studies are of limited utility in elucidating the mechanism(s) of leukemogenic effect.
Furthermore, the solid tumors seen in the animal studies have not been reported in humans
exposed to benzene, and therefore, the carcinogenic effects seen in animals have questionable
relevance for humans.
The chronic toxicity/carcinogenicity studies conducted by the NTP via the oral route are the
most thorough studies performed to date; the carcinogenic effects are described below. The
experimental procedures for both mouse and rat have been described under chronic toxicity.
Rat: In male rats, benzene caused increased incidences of Zymbal gland carcinomas,
squamous cell papillomas and carcinomas of the oral cavity, and squamous cell papillomas and
squamous cell carcinomas of the skin. These effects were dose-related, and increased
incidences were statistically significant at the lowest dose (36 mg/kg/day). In female rats,
benzene caused increased incidences of Zymbal gland carcinomas, and squamous cell
papillomas and squamous cell carcinomas of the oral cavity. These effects were dose related;
for the Zymbal gland, statistical significance was seen at the lowest dose (18 mg/kg/day), and
for the oral cavity, significance was reached at 36 mg/kg/day.
Mouse: In the male mouse, benzene caused increased incidences of Zymbal gland squamous
cell carcinomas, malignant lymphomas, alveolar/bronchiolar adenomas and carcinomas
(combined), Hardarian gland adenomas and carcinomas (combined), and squamous cell
carcinomas of the preputial gland. These effects were dose related. For the Hardarian gland
adenomas and carcinomas combined, significance was reached at 18 mg/kg/day, and for other
tumors, significance was reached at 36 mg/kg/day. In the female mouse, benzene caused
increased incidences of malignant lymphomas, ovarian granulosa cell tumors and carcinomas,
carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas,
alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. All effects of
benzene were dose-related. Significance was reached at 36 mg/kg/day for lymphoma, ovarian
granulosa cell tumors and carcinomas, carcinomas of the mammary gland, and
alveolar/bronchiolar carcinomas. For Zymbal gland carcinomas and alveolar/bronchial
adenomas, significance was reached at 71 mg/kg.
Benzene VCCEP Submission
March 2006
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