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

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<strong>IARC</strong> MONOGRAPHS VOLUME 79
phenobarbital continuously in the drinking-water until 36 weeks of age. Three animals
from each group were killed at 4, 20 <strong>and</strong> 28 weeks, <strong>and</strong> six animals from each group
were killed at 12, 36 <strong>and</strong> 44 weeks of age. Half of the remaining animals were killed at
52 weeks <strong>and</strong> the remainder at 60 weeks of age. NDEA alone induced multiple focal
hepatic lesions, including hepatocellular foci, adenomas (average, 34/mouse at 44
weeks, 16/mouse at 52 weeks <strong>and</strong> 13/mouse at 60 weeks) <strong>and</strong> carcinomas (3/mouse at
44 weeks, 8/mouse at 52 weeks <strong>and</strong> 12/mouse at 60 weeks). Subsequent exposure to
phenobarbital suppressed the development of focal hepatic lesions, decreased the
number of adenomas (5/mouse at 44 weeks, 6/mouse at 52 weeks <strong>and</strong> 8/mouse at 60
weeks) <strong>and</strong> carcinomas (0 at 44 weeks, 0 at 52 weeks <strong>and</strong> 1/mouse at 60 weeks) <strong>and</strong>
prolonged the latency or significantly slowed the rate at which hepatocellular tumours
developed in these mice (Diwan et al., 1984).
Groups of CD-1 mice [initial numbers unspecified; sex ratio presumably equal], 15
days of age, received an intraperitoneal injection of 0, 5 or 20 mg/kg bw N-ethyl-Nnitrosourea
(ENU). At 5 weeks of age, they received 500 mg/L sodium phenobarbital in
the drinking-water until 51 weeks of age, <strong>and</strong> the experiment was terminated 1 week
later. ENU induced lung <strong>and</strong> liver tumours in a dose-dependent fashion. <strong>Sodium</strong> phenobarbital
promoted the hepatocarcinogenesis initiated by ENU in females (at the high
dose of ENU: 6/33 adenomas (p ≤ 0.01), 7/33 carcinomas (p ≤ 0.01; adenomas plus
carcinomas); at the low dose of ENU: 4/32 adenomas (p ≤ 0.05), 2/32 carcinomas;
(p ≤ 0.05; adenomas plus carcinomas); ENU alone: no liver tumours). Males were more
susceptible than females to the carcinogenicity of ENU, <strong>and</strong> subsequent treatment with
sodium phenobarbital increased the hepatocellular carcinoma incidence (high dose of
ENU: 22/30 adenomas <strong>and</strong> 10/30 carcinomas; low dose of ENU: 8/39 adenomas <strong>and</strong>
2/39 carcinomas; high dose of ENU plus sodium phenobarbital: 22/25 adenomas, 17/25
carcinomas (p ≤ 0.05); low dose of ENU plus sodium phenobarbital, 14/36 adenomas,
10/36 carcinomas; p ≤ 0.01). Subsequent treatment with sodium phenobarbital also
promoted the development of spontaneous liver tumours. <strong>Sodium</strong> phenobarbital
treatment did not, however, alter the incidence of lung tumours induced by ENU (Pereira
et al., 1985).
In a study to compare the effect of sodium phenobarbital on the development of liver
tumours in juvenile <strong>and</strong> adult mice, 6-week-old male B6C3F 1 mice (20–24 per group)
received 15 or 45 mg/L NDEA in the drinking-water for 4 weeks. One week later, they
were given 500 mg/L sodium phenobarbital in the drinking-water until termination of
the study at 50 weeks of age. In a second experiment, 15-day-old male BALB/c <strong>and</strong>
B6C3F 1 mice received a single intraperitoneal injection of 25 mg/kg bw NDEA or the
vehicle alone. At 4 weeks of age, they were given 500 mg/L sodium phenobarbital in the
drinking-water until 20 or 28 weeks of age. In the first experiment, both concentrations
of NDEA induced hepatocellular adenomas (25 <strong>and</strong> 65%, respectively) <strong>and</strong> carcinomas
(13 <strong>and</strong> 30%, respectively). Subsequent treatment with sodium phenobarbital increased
the incidence of both hepatocellular adenomas (100% with both initiating concentrations
of NDEA; p ≤ 0.01 at 15 mg/L) <strong>and</strong> carcinomas (81 <strong>and</strong> 70% at 45 <strong>and</strong> 15 mg/L of