(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

induce solid tumors in animals in the Zymbal gland of rats, as well as forestomach, preputial
gland, oral and nasal tumors, and mammary tumors; humans do not get benzene-induced solid
tumors. DNA adducts have not been identified in target organs for tumors, but Angelosanto et
al. (1996) did detect chromosome damage, expressed as increased incidence of
micronucleated cells in primary cultures of epithelial cells from rat Zymbal explants, following in
vivo oral exposure to benzene for 3 days at doses of 12.5—250 mg/kg/day in female Sprague
Dawley rats and 1—200 mg/kg/day in male Fischer 344 rats.
6.2.2.6 Summary of genotoxic data
The genotoxic potential of benzene and its metabolites has been studied extensively. More
than 220 publications with original data have been evaluated and reviewed by regulatory
organizations (ATSDR, 1993, 1997; IRIS, 1998; EPA-NCEA, 1998; ECB, 2003) for mutagenic
significance and in relation to benzene-induced cancer. In vitro studies have demonstrated that
benzene does not generally induce gene mutation in standard bacteria and in vitro mammalian
cell systems, but that metabolites produced by exogenous or endogenous activation can
produce positive results in some systems. Benzene exposure did result in structural and
numerical chromosome abnormalities in mammalian cells in culture or in laboratory animals.
Significant chromosome aberrations in humans usually occurred at exposure levels sufficient to
produce toxicity to the hematopoietic system. Cytogenetic effects were expressed as
chromosome breakage and aberrations, increased incidence of micronucleated polychromatic
and/or normochromatic erythrocytes in bone marrow or peripheral blood, and as sister
chromatid exchanges. DNA damage, measured by single-strand breaks, was also identified in
blood of exposed mice. Whysner (2000) and Whysner et al. (1995) suggested that the
mechanism for benzene-induced clastogenicity and leukemogenesis involves inhibition of
topoisomerase II, an enzyme involved in DNA replication. Formation of a stable benzenetopoisomerase
II-DNA complex could produce the SCE, nonhomologous recombination, gene
deletion, and rearrangements seen in benzene genotoxicity. Other proposed mechanisms have
included DNA-reactive benzene metabolites forming adducts or cross-links, oxidative DNA
damage leading to strand breaks and missense mutations, and aneugenesis due to damage to
components of mitotic apparatus.
6.2.3 Reproductive and Developmental Toxicity
6.2.3.1 Reproductive Toxicity
The potential for benzene to affect the reproductive system is available from animal studies
found in the literature. These studies include a female rat fertility study (Kuna et al., 1992), a
dominant lethal assay in rats (API, 1980), the evaluation of reproductive organs in repeat-dose
systemic toxicity studies (Wolf, 1956; Ward et al., 1985; NTP, 1986), and two early Russian
studies involving exposure of rats prior to impregnation and during pregnancy (Gofmekler, 1968;
Vozovaya, 1975, 1976).
The ability of benzene to affect the process of producing viable gametes in sexually mature
animals has been reported in several studies. In Kuna, et al. (1992), the effects of benzene
(99.96% purity) exposure on fertility in female Sprague Dawley rats exposed at vapor
concentrations of 0, 1, 30, and 300 ppm (0, 3.2, 96, and 958 mg/m 3 ), 6 hours/day, 5 days/week
for 10 weeks premating and mating, then daily from gestation day (GD) 0–20 and lactation days
5–20 were assessed. No treatment-related effects were observed on maternal mortality, estrus
cycle, body weight and body-weight changes, physical parameters, pregnancy rate, length of
Benzene VCCEP Submission
March 2006
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