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

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204 <strong>IARC</strong> MONOGRAPHS VOLUME 79 47 weeks of age. At 33 weeks, 9/10 D2B6F 1 mice given NDEA followed by phenobarbital had hepatocellular adenomas (3.8 ± 1.0/mouse) versus 2/10 (1.0 ± 0) with NDEA alone. Administration of phenobarbital significantly increased the incidence (from 30% to 100%, p < 0.05) <strong>and</strong> the number of tumours (average number, 5.2 versus 2.0/mouse, p < 0.05) initiated by NDEA in the reciprocal F 1 cross B6D2F 1 mice. By 47 weeks, all mice of reciprocal F 1 hybrids D2B6F 1 <strong>and</strong> B6D2F 1 that had received phenobarbital after administration of NDEA had multiple hepatocellular tumours, including both adenomas (12.5 <strong>and</strong> 15/mouse, respectively) <strong>and</strong> carcinomas (2.6 <strong>and</strong> 2.7/mouse, respectively). Thus, the susceptibility to promotion of hepatocarcinogenesis by phenobarbital was a dominant trait in crosses between DBA/2 <strong>and</strong> C57BL/6, <strong>and</strong> the two reciprocal F 1 hybrids responded similarly to promotion by phenobarbital. Interestingly, however, 8/10 D2B6F 1 mice but only 1/10 B6D2F 1 mice given phenobarbital after NDEA developed single or multiple (1.75 ± 0.4) hepatoblastomas between 33 <strong>and</strong> 47 weeks. No hepatoblastomas were found in mice given only NDEA or phenobarbital (Diwan et al., 1989b). Eight groups of 30 male weanling C3H/HeN mice were given either a normal diet or a diet containing 1.0% choline chloride, 1.5% DL-methionine or both DL-methionine <strong>and</strong> choline chloride with or without 0.05% phenobarbital for 52 weeks. A further eight groups of 30 mice each were given a single intraperitoneal injection of 150 mg/kg bw NDEA <strong>and</strong> received the same dietary supplements with or without 0.05% phenobarbital. Treatment with NDEA resulted in a 63% suppression in the body weight gained at 15 weeks (maximum growth period) when all groups of mice receiving NDEA were combined <strong>and</strong> compared with all groups not receiving NDEA (6.0 versus 16.2 g weight gain, respectively [no p value given]). NDEA decreased the survival time of mice in all treated groups (p < 0.005 compared with untreated controls) except for one NDEA-treated group without phenobarbital <strong>and</strong> supplemented with methionine only. The first death from liver cancer occurred at 20 weeks after initiation for the group given NDEA plus phenobarbital, at 25 weeks for the group given NDEA only, at 42 weeks for that given phenobarbital only <strong>and</strong> at 49 weeks for the untreated control group. Animals given phenobarbital only with both methionine <strong>and</strong> choline had longer survival than mice receiving no supplementation when analysed on the basis of deaths with tumours (p < 0.0005). Groups receiving the initiating dose of NDEA <strong>and</strong> no phenobarbital showed similar trends. Combined treatment with methionine lowered the relative liver weights of the mice given NDEA plus phenobarbital from 19.5% ± 1.6 to 13.8% ± 1.5 of body weight (p < 0.05). Treatment with phenobarbital only resulted in incidences of hepatocellular carcinoma of 79% in animals on the normal diet, 74% in those on choline-supplemented diet, 60% with methionine supplementation <strong>and</strong> 31% with methionine plus choline supplementation. In mice initiated with NDEA <strong>and</strong> promoted with phenobarbital, dietary supplementation with methionine <strong>and</strong> choline also protected against the formation of liver carcinomas; however, the total incidence of liver tumours (adenomas <strong>and</strong> carcinomas) was not altered. Metastases of hepatocellular carcinomas to the lungs were
PHENOBARBITAL AND ITS SODIUM SALT 205 found only in mice receiving NDEA plus phenobarbital; the incidence was reduced from 16% in the group receiving no supplement to 6% in the group receiving choline supplementation <strong>and</strong> to 0% in groups of mice receiving diets supplemented with methionine alone or with choline <strong>and</strong> methionine (Fullerton et al., 1990). To confirm the promoter-dependent development of hepatoblastomas in mice, groups of 30 male D2B6F 1 mice, 5 weeks of age, were given a single intraperitoneal injection of 90 mg/kg bw NDEA <strong>and</strong> then 2 weeks later were given either a normal diet or a diet containing 500 mg/kg phenobarbital for 53 weeks. Mice exposed to NDEA alone <strong>and</strong> to phenobarbital alone were maintained for 110 weeks. Hepatocellular tumours (adenomas <strong>and</strong> carcinomas) occurred in 97% of D2B6F 1 mice given NDEA alone. The incidence of hepatocellular carcinomas in NDEA-treated mice (37%) was significantly enhanced by subsequent administration of phenobarbital (96%). Multiple hepatocellular adenomas <strong>and</strong> carcinomas developed in 77% of mice exposed to phenobarbital alone. Only 10% of the mice treated with NDEA alone developed hepatoblastomas, while subsequent administration of phenobarbital resulted in an increased incidence (77%) <strong>and</strong> multiplicity (2.8 ± 1.5) of such tumours. Multiple hepatoblastomas also occurred in 11/30 (37%) mice that received phenobarbital only. Thus, in D2B6F 1 mice, the development of hepatoblastoma from <strong>its</strong> precursor cells (adenoma <strong>and</strong> carcinoma cells) is strongly increased in the presence of a promoting agent (Diwan et al., 1995). (b) Studies in juvenile mice Groups of male <strong>and</strong> female pups of DDD strain mice [total initial number not given] were given either an intraperitoneal injection of 0.025 mL of 0.12% N-nitrosodimethylamine (NDMA) 24 h after birth followed by 0.05% phenobarbital in the drinking-water from 4 weeks of age (36 newborn mice), NDMA alone (24 newborn mice), a single intraperitoneal injection of saline (0.9% NaCl) followed by phenobarbital (38 newborn mice) or a single intraperitoneal injection of saline alone (24 newborn mice). The experiment was terminated 16 weeks after birth. Survival was not affected in any group. Liver tumours occurred in 27/35 (77%) mice exposed to NDMA plus phenobarbital, with a multiplicity of 4.3 per mouse. Twenty-four had type A tumours (simple nodular growth of liver parenchymal cells) <strong>and</strong> three male mice had type B tumours (areas of papilliform or adenoid growth of tumour cells with a distorted parenchymal structure). None of the tumours metastasized. In mice that received NDMA alone, liver tumours (all type A) occurred in 8/24 (33%) mice, with an average number of 0.4 tumours per mouse. No sex difference was found in the incidence, type or multiplicity of tumours in mice given NDMA alone or NDMA plus phenobarbital. None of the mice exposed to saline <strong>and</strong> phenobarbital or saline alone developed tumours (Uchida & Hirono, 1979). [The Working Group noted the short duration of exposure.] Groups of 40 male B6C3F1 mice, 15 days of age, were given a single intraperitoneal dose of 5 mg/kg bw NDEA. Starting 2 weeks later, groups of mice received 500 mg/L
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these tumours was a CG → AT trans
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5. Summary of Data Reported <strong
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