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210 of hepatocellular carcinomas were significantly greater in those receiving NDEA plus phenobarbital (number, 11.7 ± 1.0 versus 4.0 ± 1.1, p < 0.001; volume %, 54.2 ± 3.6 versus 20.8 ± 5.5, p < 0.001). Adenomas <strong>and</strong> preneoplastic foci were induced by phenobarbital alone at week 23, while only one control MT42 mouse developed foci at that time. By week 37, 5/5 MT42 mice given NDEA only <strong>and</strong> 2/6 given phenobarbital only had developed hepatocellular carcinomas <strong>and</strong> adenomas. In CD-1 mice, NDEA initiation <strong>and</strong> phenobarbital promotion significantly increased the numbers per liver <strong>and</strong> volume per cent of adenomas <strong>and</strong> foci at 23 weeks when compared with those given NDEA alone (number of foci, 30.7 ± 9.8 versus 5.4 ± 3.8, p < 0.05; foci volume, 0.16% ± 0.06 versus 0.03% ± 0.02, p < 0.05; number of adenomas, 4.1 ± 1.4 versus 0.6 ± 0.3, p < 0.05). No tumours or adenomas were found in CD-1 mice given NDEA alone or phenobarbital alone. The number per liver <strong>and</strong> volume per cent of hepatocellular carcinomas in MT42 mice given NDEA only or NDEA plus phenobarbital were significantly higher than those in CD-1 mice at weeks 23 <strong>and</strong> 37. The proliferating cell nuclear antigen-labelling indices of the foci <strong>and</strong> adenomas in MT42 mice given NDEA alone or NDEA plus phenobarbital were significantly higher than those in CD-1 mice (Tamano et al., 1994). [The Working Group noted the inadequate number of animals per group.] 3.3.2 Promotion in rat liver <strong>IARC</strong> MONOGRAPHS VOLUME 79 (a) Effects of subsequent administration of phenobarbital Groups of (SD/Anl[Anl 66]) rats [initial number, sex <strong>and</strong> age not specified] were given diets containing 0.02% 2-acetylaminofluorene (AAF) for 11, 16, 21 or 26 days. At each of these intervals, 36 rats were transferred to the control diet <strong>and</strong> another 36 were transferred to a diet containing 0.05% phenobarbital. Four rats from each group were killed at 21-day intervals starting 91 days after the beginning of the experiment. The subsequent treatment with phenobarbital for up to 260 days increased the incidence of hepatomas at each of the four periods of AAF treatment (AAF 11 days, 2/105; AAF 11 days followed by phenobarbital, 17/106; AAF 16 days, 7/101; AAF 16 days followed by phenobarbital, 42/104; AAF 21 days, 18/103; AAF 21 days followed by phenobarbital, 64/102; AAF 26 days, 27/103; AAF 26 days followed by phenobarbital, 86/108; two-way analysis of variance for duration of AAF feeding, p < 0.05 <strong>and</strong> for phenobarbital treatment, p < 0.01). At each sacrifice interval, more rats given both AAF <strong>and</strong> phenobarbital had tumours. The hepatomas found at the early sacrifice intervals were seen only in the groups that had been fed AAF for the two longer periods (Peraino et al., 1971). To investigate the effects of varying the time of exposure to phenobarbital on enhancement of hepatocarcinogenesis, groups of 106–109 male Sprague-Dawley rats, 22 days of age, were given diets containing 0.02% AAF for 3 weeks <strong>and</strong> were then fed a diet containing 0.05% phenobarbital for various times: AAF diet for 18 days then phenobarbital diet; AAF diet for 18 days then phenobarbital diet for 5 days then control
PHENOBARBITAL AND ITS SODIUM SALT 211 diet; AAF diet for 18 days then phenobarbital diet for 20 days then control diet; AAF diet for 18 days then control diet for 10 days then phenobarbital diet; AAF diet for 18 days then control diet for 30 days then phenobarbital diet. Beginning 101 days after the cessation of AAF feeding, 12 rats from each experimental group were killed at 3-week intervals <strong>and</strong> examined for tumours. Continuous treatment with phenobarbital, beginning immediately after 18 days of AAF feeding caused a threefold increase (73/109 versus 22/106) in the incidence of tumours of all sizes <strong>and</strong> an eightfold increase in that of larger (≥ 10 mm) tumours (46/109 versus 5/106). Treatment with phenobarbital for only 5 days had no effect on the incidence of tumours but produced a 60% increase in the number of animals with larger tumours (8/106 versus 5/106). When administration of phenobarbital was increased to 20 days, it had a slightly greater effect (35/108 versus 22/106). In rats that received normal diet for 10 days <strong>and</strong> then phenobarbital, the effect on tumour incidence was similar to that in animals that received phenobarbital in the diet immediately after 18 days of AAF feeding (78/108 versus 73/109). When the treatment-free interval was increased to 30 days, a slight reduction was seen in the enhancing effect of phenobarbital (68/106 versus 73/109). When tumours of all sizes were taken into account, the rates of increase in the percentage of rats with tumours were parallel in the groups given AAF <strong>and</strong> AAF plus phenobarbital after 120 days, the tumour incidence in the latter group being threefold greater than that in the AAF group. The percentage of rats with larger tumours, however, increased at a higher rate in the group given AAF plus phenobarbital than in that given AAF. An increased rate of appearance of new tumour foci was also seen in rats given AAF plus phenobarbital, the largest increase occurring for tumours ≥ 10 mm (Peraino et al., 1973b). [The Working Group noted that no statistical analysis was provided.] Groups of male Donryu rats [initial numbers not specified], 21 days old, were fed a basal diet containing 600 mg/kg 3′-methyl-4-(dimethylamino)azobenzene (3′-Me- DAB) for the first 3 weeks <strong>and</strong> then a diet containing 5–500 mg/kg phenobarbital. Groups of 5–10 animals were killed at 12 <strong>and</strong> 24 weeks of age. A dose-dependent effect of phenobarbital was clearly seen on both the number <strong>and</strong> size of enzymealtered isl<strong>and</strong>s at concentrations > 10 mg/kg of diet. The increase in the total number of isl<strong>and</strong>s in these groups was significant (p < 0.05 or 0.01). The numbers of enzymealtered isl<strong>and</strong>s in the largest size class (about 1000 μm) were significantly increased at 100 <strong>and</strong> 500 mg/kg of diet (p < 0.05 <strong>and</strong> < 0.01, respectively), while those in the next two lower size classes (500–999 <strong>and</strong> 250–499 μm) were significantly increased at the highest dietary concentration (p < 0.01) (Kitagawa et al., 1984). [The Working Group noted the small number of animals per group <strong>and</strong> the short duration of exposure.] (b) Effects of simultaneous administration of phenobarbital Six groups of 50 (SD/AnI[AnI66]) rats received either normal diet or a diet containing 0.05% phenobarbital, 0.01% AAF, 0.05% phenobarbital plus 0.01% AAF,
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5. Summary of Data Reported <strong
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