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Animal Studies
Available experimental data prior to 1976 has been summarized by Maltoni et al. (1983). These earlier
studies did not provide evidence for carcinogenicity in animals. Since then two significant series of
bioassay studies have been reported, those of Maltoni et al. (1983) and the National Toxicology
Program (NTP, 1983).
In a series of oral studies, reported by Maltoni et al. (1983), rats were administered benzene via gavage
tube. Male and female Sprague-Dawley rats were administered benzene at 0, 50 or 250 mg/kg
benzene in olive oil, 4 to 5 times per week, for 52 weeks. Dose-related increases were observed for
Zymbal gland carcinoma in the female rats only. In Sprague-Dawley rats administered 0 and 500 mg/kg
benzene in olive oil, 4 to 5 times per week for 104 weeks significant increases relative to controls were
reported for Zymbal gland carcinoma (males and females), and oral cavity carcinoma (males and
females).
Maltoni et al. (1983) also chronically exposed pregnant Sprague-Dawley rats (breeders) and their
offspring to high concentrations of benzene using a complex dosing regimen. Exposure concentrations
ranged from 200 to 300 ppm. Among the breeders, a slight increase (not significant) in the incidences
of Zymbal gland carcinoma and mammary tumors were reported. Among offspring, significant
increased incidences in Zymbal gland tumors and non-significant increases in cancers of oral and nasal
cavity, mammary gland and liver were reported. Selected study data are listed in Table 2.
Table 2:
Organ (Site)
Maltoni et al. (1983) benzene rat bioassay summary
Tumor Type Route of
Exposure
Sex
Zymbal gland carcinomas gavage 1 F
Hemolymphoreticular
‘leukemias’ gavage 1 M
Mammary carcinomas gavage 1 F
Zymbal gland carcinomas
Oral Cavity
carcinomas
carcinomas
carcinomas
gavage 2
gavage 2
gavage 2
gavage 2
F
M, F
M
M, F
13.9
66.7
13.9
66.7
13.9
66.7
321.4
321.4
321.4
321.4
Dose
(mg/kgday)
Cochran-
Armitage Linear
Trend Test
p < 0.001
----
----
p = 0.005
----
----
p = 0.091
----
----
N/A
(single dose level)
N/A
(single dose level)
Zymbal gland carcinomas inhalation 3 F 17 N/A
(single dose level)
Fisher Exact
Test
p = 0.25
p = 0.003
p = 1.0
p = 0.078
p = 0.5
p = 0.178
p = 0.007
p < 0.001
p = 0.003
p < 0.001
Difference in Cancer
Attack Rate per 100
(Dose-Control)
6.7
25.0
0.0
12.1
3.3
11.9
15.0
14.0
17.5
13.7
p = 0.27 3.9
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