(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

petroleum fractions dissolved in benzene to facilitate dermal administration. At present, there is
no acceptable animal model for the human leukemogenic effects. Recently, French and
Saulnier (2000) reported that leukemia can be produced in the TgAC mouse after dermal
administration of benzene. However, it is not known whether experiments with this mouse will
ultimately yield a satisfactory model.
In animal studies, responses to benzene administration are variable and may depend on a
variety of factors, including species, strain, exposure duration, and whether exposure is
intermittent or continuous. Serious toxicological effects are primarily confined to hematological
parameters and involve all aspects of the hematopoietic system, from depression of stem cells
up to pancytopenia and histopathological alterations in the marrow. Effects have been
observed after acute, sub-acute, subchronic, and chronic exposure via different routes of
administration. However, AML, which is of primary concern in humans, is not produced reliably
in standard laboratory test species, and occasional reports of cancer in experimental animals
(usually the mouse) are of questionable value in cancer risk assessments. The subchronic
toxicity of benzene has been studied primarily in the mouse and rat. Depending on the level of
dosing, the effects are hematotoxicity, reduction in body-weight gain, and death. Effects on
body weight and mortality may be secondary to hematotoxicity. Thus, hematotoxicity is the
parameter for quantifying toxic effects of benzene and for estimating risk from exposure. The
hematotoxicity in the rodent appears to compare well with benzene-induced hematologic
changes in cases of human exposure.
Results of benzene-induced mortality and hematotoxicity in key rodent studies conducted by
inhalation and oral routes of exposure are summarized below. Information was obtained mainly
from several major reviews of benzene toxicity (ATSDR, 1997; U.S. EPA, 1998a, 2003a).
Inhalation (see Table 6.4)
Mortality: In the rat, exposure of males and females to 200 ppm, 4–7 hours/day, 4–
5 days/week, caused significant mortality (Maltoni et al., 1983, 1985). In the mouse, deaths
occurred in males and females at 300–302ppm, 6 hours/day, 5 days/week, for 16–26 week
(Cronkite et al., 1985; Cronkite et al., 1989; Farris et al., 1993; Green et al., 1981a,b).
Hematological Effects: Mouse and rat studies were identified that evaluated effects on
peripheral blood and/or hematopoiesis (IRIS, 1998). Only one of the rat studies was performed
over a dose range, and the results are considered here as being representative of effects in the
rat. Male and female rats (10 M, 10 F/group) were exposed to benzene at concentrations of 0,
1.0, 100, and 300 ppm, 6 hours/day, 5 days/week for up to 90 days, with serial sacrifice after 7,
14, 28, 56, and 91 days of exposure. Results showed significant decreases in WBC counts in
males (day 14), and females (days 14–19) and slightly decreased femoral cellularity at
300 ppm.
Of the mouse studies, only one was performed over a dose range in both males and females.
Results are consistent with other single-sex and single-dose studies and are considered to be
representative of effects in the mouse in standard-protocol toxicity studies. In this assay,
groups of 30 male and 30 female mice were exposed at 0, 1.0, 3.0, 30, and 300 ppm,
6 hours/day, 5 days/week for up to 91 days, with serial sacrifices after 7, 14, 28, 56, and 91
days of exposure (Ward et al., 1985). Hematological effects were not observed at 1, 10, or
30 ppm. However, at 300 ppm, mice showed reduced hematocrit, total hemoglobin
concentration, RBC count, WBC count, platelet count, myeloid/erythroid ratios, and percent of
lymphocytes. Red blood cells had increased mean corpuscular volume, mean cell hemoglobin,
Benzene VCCEP Submission
March 2006
83