(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

micronucleated polychromatic erythrocytes, while transgenic mice did not exhibit changes in
cellularity or micronucelated-PCE.
Oral exposure to benzene produces comparable significant increases in chromosome
aberrations, and also demonstrates that male mice appear to be more sensitive than female.
Oral administration of 440 and 879 mg/kg/day benzene for 3 days to male and female CD-1
mice resulted in significantly elevated frequencies of chromosomal aberrations and micronuclei
in bone marrow. Male mice responded at 440 mg/kg, while 879 mg/kg was needed to elicit a
response in females (Meyne and Legator, 1980). Siou et al. (1981) demonstrated that Chinese
hamsters (both sexes) are less sensitive to benzene clastogenicity. Administration of 2198 or
8790 mg/kg/day for 2 days did not induce a significant increase in micronuclei in bone marrow
cells, and chromosome aberrations were observed only in males after 2 days exposure at
8790 mg/kg. Swiss mice in the same study, given doses of 0, 56.2, 141, 352, and
2189 mg/kg/day for 2 days produced significant dose-dependent increases in chromosome
aberrations and micronuclei, with males being the more sensitive. Fujie et al. (1992) examined
dose-effect and time-effect relationships and sex and strain differences using Wistar, Sprague
Dawley, and Long Evans rats. The incidence of aberrant cells increased progressively with
time, reaching a maximum response of 65% aberrant cells at 12 hours after treatment with
750 µL/kg (660 mg/kg) in male Long Evans rats: lowest-observed-effect level (LOEL) =
15 µL/kg (132 mg/kg). Increased micronuclei in normochromatic peripheral blood erythrocytes
were reported by Au et al. (1990) after oral treatment at 26.6–146.6 mg/kg body weight for 2, 8,
or 14 days. Further increases in frequency were observed after cessation of treatment, with the
strongest effect at 36 weeks from start of treatment. In a retrospective analysis of peripheral
blood smears from the NTP oral cancer study in B6C3F1 mice, Choy et al. (1985) reported a
significant dose-dependent elevation in micronucleated-NCE at doses of 50 mg/kg/day over
2 years. At each dose and sampling time, frequency was higher in males than in females.
MacGregor et al. (1990) also reported induction of micronuclei in normochromatic erythrocytes
of mice with oral long-term exposure. After 4 months exposure, a dose-dependent increase in
micronuclei frequency was found over a dose range of 25—600 mg/kg, with effects in males
more pronounced than in females: NOEL females = 25 mg/kg; LOEL males = 25 mg/kg. After
1–2 years of treatment, male rats still showed increased micronuclei frequencies, although the
magnitude of response decreased with exposure time; females were not evaluated.
Benzene VCCEP Submission
March 2006
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