Phenobarbital and its Sodium Salt - IARC Monographs on the ...

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<strong>IARC</strong> MONOGRAPHS VOLUME 79
in extremis or at the end of the respective experiments, i.e. at 91 weeks for C3H/He
<strong>and</strong> 100 weeks for the C57BL/6 mice. In addition, 25 animals of each strain were
treated for 60 weeks <strong>and</strong> then returned to the control diet, <strong>and</strong> the survivors were killed
at the end of the respective experiments. Nodules were seen in both treated <strong>and</strong> control
C3H/He mice as early as 30 weeks, <strong>and</strong> were numerous in both these groups at the
final kill at 91 weeks. In control animals, all the nodules were of the basophilic type,
while in the treated group both basophilic <strong>and</strong> eosinophilic nodules were found. The
majority of treated animals bore eosinophilic nodules. By 91 weeks, 80% (16/20) of
the control animals <strong>and</strong> 40% (8/20) of the treated animals bore basophilic nodules,
while all the treated animals <strong>and</strong> none of the controls (0/20) also developed multiple
eosinophilic nodules (20/20). C3H/He mice given sodium phenobarbital for 60 weeks
<strong>and</strong> then returned to the control diet bore fewer nodules at 91 weeks than treated mice
killed at 60 or 91 weeks. Nodules did not develop in C57BL/6 mice until week 60 in
the treated group <strong>and</strong> not until week 100 among control animals. In C57BL/6 mice
treated with sodium phenobarbital, 2/20 mice developed eosinophilic nodules by week
60, <strong>and</strong> 50% of them bore this type of nodule at 100 weeks; however, fewer eosinophilic
nodules were found than in C3H/He mice at 91 weeks (26 in 10 C57 BL/6 mice
versus 68 in 20 C3H/He mice). The cumulative incidence of carcinomas in control
C3H/He <strong>and</strong> C57BL/6 mice was 28 <strong>and</strong> 4%, respectively. The incidence of carcinomas
was not increased by treatment with sodium phenobarbital in either strain (30% in
C3H/He <strong>and</strong> 5% in C57BL/6 treated mice). The authors concluded that the two strains
of mouse reacted in a qualitatively similar manner to administration of sodium phenobarbital,
although they showed considerable quantitative differences in terms of the
time <strong>and</strong> number of nodules (Evans et al., 1992).
Genetically modified mouse: Groups of single transgenic c-myc mice (overexpressing
the c-myc oncogene), double transgenic c-myc/HGF mice (overexpressing
c-myc <strong>and</strong> co-expressing the hepatocyte growth factor) <strong>and</strong> wild-type mice [initial
numbers <strong>and</strong> sex not specified] were given a diet containing 0.05% phenobarbital from
3 weeks to 10 months of age. At 6 months, the incidence of hepatocellular adenomas
was 5/10 in c-myc mice fed phenobarbital, 0/5 in wild-type mice <strong>and</strong> 0/10 in c-myc
mice on basal diet. At 8 months, the incidence of hepatocellular adenomas was 8/10 in
c-myc mice fed phenobarbital, 0/5 in wild-type mice <strong>and</strong> 2/10 in c-myc mice on basal
diet. At 10 months, the incidence of hepatocellular adenomas was 10/10 in c-myc mice
fed phenobarbital, 0/5 in wild-type mice <strong>and</strong> 4/12 in c-myc mice on basal diet. At 8
months, hepatocellular carcinoma occurred only in c-myc mice fed phenobarbital
(2/10). At 10 months, the incidence of hepatocellular carcinomas was 4/10 in c-myc
mice fed phenobarbital, 0/5 in wild-type mice <strong>and</strong> 1/12 in c-myc mice fed basal diet. In
contrast to the single transgenic c-myc mice, no liver tumours were found in 10 c-myc/
HGF mice killed at 6, 8 or 10 months after treatment with phenobarbital, nor were there
any liver tumours in the control c-myc/HGF animals (10 mice killed at 6 <strong>and</strong> 8 months
<strong>and</strong> 12 mice at 10 months) (Thorgeirsson & Santoni-Rugiu, 1996; Thorgeirsson et al.,
1997).