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animals. There were no survivors among the animals receiving 3.5 mg benzidine. Miakawa and
Yoshida (1975) fed female dd strain mice (50/group) diet containing either 0 or 0.2% benzidine for 280
days. Hepatocellular carcinomas were identified in 11 of 32 mice surviving 140 days or more, whereas
no hepatocellular carcinomas were reported among control mice. The significance level of the
difference in incidence was p < 0.001 by Fisher’s exact test.
Littlefield et al.(1984) exposed male and female F 1 generation mice (BALB/c males × C57BL females)
to benzidine in drinking water for life (~33 months). Mice from a cross of F 1 generation males and
females were also exposed as above . Exposure levels and incidence of hepatocellular carcinomas are
presented in Table 1. Significant differences in the incidence of hepatocellular carcinoma were observed
in all exposed groups (p < 0.05, Fisher’s exact test). Frith et al. (1980) also exposed F 1 and F 2
generation mice (BALB/c males × C57BL/6 females) to 30-400 ppm benzidine dihydrochloride in
drinking water for 40, 60, or 80 weeks at which time animals were sacrificed. As in the Littlefield et al.
(1984) study, animals showed a dose-dependent increase in hepatocellular carcinoma incidence. This
effect was also shown to be dependent upon duration of exposure.
Table 1. Incidence of hepatocellular carcinoma in F 1 and F 2 generation mice (BALB/c ×
C57BL) exposed to benzidine in drinking water (Littlefield et al., 1984).
hepatocellular carinoma incidence
males
females
exposure level F 1 F 2 exposure level F 1 F 2
(ppm)
(ppm)
0 14/125 17/123 0 3/124 10/125
30 24/119 20/118 20 51/120 54/119
40 30/96 20/95 30 52/95 43/95
60 32/71 23/72 40 45/72 31/71
80 35/71 24/71 60 55/71 37/72
120 61/71 37/71 80 60/69 51/69
160 49/71 32/71 120 64/72 56/72
Vesselinovitch et al. (1975) treated male B6C3F 1 mice with feed containing 150 ppm benzidine
dihydrochloride from weeks 6 to 45 of life. Groups of 50 mice thus treated were sacrificed at 45, 60,
75, or 90 weeks and examined for liver tumors. Hepatoma incidence was reported to be 8/50, 20/50,
31/50, and 35/50, respectively, at successive sacrifice times, while only one hepatoma was found
among 98 control animals sacrificed at 90 weeks (p < 0.001; Fisher’s exact test). Among the animals
with hepatomas, the incidence of hepatocellular carcinoma was 2/50, 5/50, 14/50, and 24/50,
respectively, at the successive sacrifice times.
Two other feeding studies have been conducted. Boyland et al. (1954) found cases of hepatocellular
carcinoma in rats fed diet containing 0.017% benzidine or benzidine plus tryptophan for life. Inadequate
study size, data on controls and poor survival, however, limit the usefulness of this study. Marhold et
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