For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 313)
Chem. Abstr. Name: 5-Ethyl-5-phenyl-2,4,6-(1H,3H,5H)pyrimidinetrione
A. Evidence for carcinogenicity to humans (inadequate)
Phenobarbital has been associated with increased frequencies of several cancers [ref: 1]. Excesses of brain tumours have been reported in studies of epileptics, most of whom were treated with phenobarbital, often in combination with other drugs [ref: 2,3]. The role of anticonvulsant therapy in the origin of these brain tumours is not clear, however, since the tumours may have been the precipitating cause of the epilepsy. In the largest study [ref: 2,4], there was an almost 12-fold excess of brain tumours in the first ten years of follow-up (45 observed, 3.8 expected) but this decreased with duration of follow-up to 1.3 (2 observed, 1.5 expected) 30 or more years following admission. A case-control study involving 84 children with brain tumours [ref: 5] showed a two-fold increase in the incidence of these tumours associated with prenatal or childhood exposure to barbiturates (mostly phenobarbital [ref: 6]). In a study of 11 169 matched case-control pairs of childhood cancers and controls, epilepsy was reported by 39 mothers of cases and 22 mothers of controls (20 and 12, respectively, having used phenobarbital). The number of brain tumours among the 39 cancers was not reported [ref: 7].
Lung cancer was reported in excess in 5834 members of a prepaid health plan prescribed phenobarbital during 1969-1973 and followed to 1976. The standardized mortality ratio (SMR) was 1.5 [95% confidence interval, 1.1-1.9]. Excesses were also found in users of pentobarbital sodium and secobarbital sodium. When users of the three drugs were considered together, the excess of lung cancer was found in both men and women, appeared to be accounted for only partly by cigarette smoking and persisted when cases diagnosed during the first two years of follow-up were excluded. There was no apparent relation with duration of use [ref: 8]. Small increases in lung cancer incidence were also observed in two cohort studies of epileptics [ref: 3,4], 'largely ascribable to tobacco' in one study [ref: 4], although the effects of smoking were not studied. In the larger of the two [ref: 4], the SMR was 1.3 [1.0-1.6]; in the other [ref: 3], it was 1.4 (0.9-2.1).
Liver cancer occurred in excess in the larger cohort study of epileptics [ref: 4] (SMR, 3.8 [2.7-4.9]). However, ten of the 13 observed cancers occurred in individuals exposed to thorotrast. Histology was available for nine of these: two were reported to be haemangiosarcomas, four, cholangiocarcinomas, one, a hepatocellular carcinoma, and two, adenocarcinomas [ref: 2]. In the other cohort study with data available [ref: 3], no primary liver tumour was observed although 0.6 cases of cancer of the liver and gall-bladder were expected.
B. Evidence for carcinogenicity to animals (sufficient)
Phenobarbital produced benign and malignant hepatocellular tumours in mice and hepatocellular tumours in rats after its oral administration [ref: 1,9,10]. Experiments with mice and rats in which phenobarbital was studied for its promoting activity included comparison groups given phenobarbital alone. Oral administration of phenobarbital enhanced the incidence of liver tumours in mice by N-nitrosodimethylamine [ref: 11] or N-methyl-N-nitrosourea [ref: 12] and of benign or malignant liver tumours induced in rats by 2-acetylaminofluorene [ref: 13-16], N-nitrosodiethylamine [ref: 17,18], 2-methyl-N,N-dimethyl-4-aminoazobenzene [ref: 19], benzo[a]pyrene [ref: 20], cycasin [ref: 21], N-hydroxy-N-formyl- or -acetylaminobiphenyl [ref: 22], N-nitroso-N-(4-hydroxybutyl) butylamine [ref: 16] or N-nitrosomorpholine [ref: 23]. In rats, oral administration of phenobarbital in combination with DDT resulted in a high incidence of liver tumours [ref: 24]. Phenobarbital enhanced the development of thyroid tumours [ref: 25,26] and of liver foci [ref: 26] induced in rats by N-nitrosodi(2-hydroxypropyl)amine and enhanced the incidences of liver foci, thyroid adenocarcinomas and forestomach carcinomas induced in rats by N-methyl-N-nitrosourea [ref: 27].
C. Other relevant data
No data were available on the genetic and related effects of phenobarbital in humans.
Neither phenobarbital nor its sodium salt induced sister chromatid exchanges, chromosomal aberrations, micronuclei or sperm abnormalities in mice treated in vivo. Phenobarbital induced chromosomal aberrations and mutation but not sister chromatid exchanges in cultured human cells. Both positive and negative results were obtained for transformation in rodent cells in vitro. Phenobarbital enhanced transformation of virus-infected rat embryo cells initiated with 3-methylcholanthrene in a two-stage transformation assay. It induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster cells, but not in cultured rat liver cells; micronuclei and aneuploidy were not induced in Chinese hamster cells. Phenobarbital induced mutation in Chinese hamster cells, but conflicting or negative results were obtained in other rodent cells. Phenobarbital and its sodium salt did not induce DNA strand breaks, and phenobarbital did not induce unscheduled DNA synthesis, in cultured rodent cells. Phenobarbital inhibited intercellular communication in human hepatoma cells and both phenobarbital and its sodium salt did so in rodent systems. Phenobarbital induced neither somatic mutation nor recombination in Drosophila; the sodium salt did not induce sex-linked recessive lethal mutations. Phenobarbital induced aneuploidy but not mutation or gene conversion in fungi. Conflicting results were obtained concerning the mutagenicity of these compounds in bacteria [ref: 28].
Phenobarbital is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Subsequent evaluation: Vol. 79 (2001) Also see previous evaluation: Vol. 13 (1977)
1. IARC Monographs, 13, 157-181, 1977
2. Clemmesen, J. & Hjalgrim-Jensen, S. (1978) Is phenobarbital carcinogenic? A follow-up of 8078 epileptics. Ecotoxicol. environ. Saf., 1, 457-470
3. White, S.J., McLean, A.E.M. & Howland, C. (1979) Anticonvulsant drugs and cancer. A cohort study in patients with severe epilepsy. Lancet, ii, 458-461
4. Clemmesen, J. & Hjalgrim-Jensen, S. (1981) Does phenobarbital cause intracranial tumors? A follow-up through 35 years. Ecotoxicol. environ. Saf., 5, 255-260
5. Gold, E., Gordis, L., Tonascia, J. & Szklo, M. (1978) Increased risk of brain tumors in children exposed to barbiturates. J. natl Cancer Inst., 61, 1031-1034
6. Gold, E.B., Gordis, L., Tonascia, J.A. & Szklo, M. (1979) Brain tumors in children exposed to barbiturates. J. natl Cancer Inst., 63, 3-4
7. Sanders, B.M. & Draper, G.J. (1979) Childhood cancer and drugs in pregnancy. Br. med. J., i, 717-718
8. Friedman, G.D. (1981) Barbiturates and lung cancer in humans. J. natl Cancer Inst., 67, 291-295
9. Feldman, D., Swarm, R.L. & Becker, J. (1981) Ultrastructural study of rat liver and liver neoplasms after long-term treatment with phenobarbital. Cancer Res., 41, 2151-2162
10. Ward, J.M. (1983) Increased susceptibility of livers of aged F344/NCr rats to the effects of phenobarbital on the incidence, morphology, and histochemistry of hepatocellular foci and neoplasms. J. natl Cancer Inst., 71, 815-823
11. Uchida, E. & Hirono, I. (1979) Effect of phenobarbital on induction of liver and lung tumors by dimethylnitrosamine in newborn mice. Gann, 70, 639-644
12. Pereira, M.A., Knutsen, G.L. & Herren-Freund, S.L. (1985) Effect of subsequent treatment of chloroform or phenobarbital on the incidence of liver and lung tumors initiated by ethylnitrosourea in 15 day old mice. Carcinogenesis, 6, 203-207
13. Watanabe, K. & Williams, G.M. (1978) Enhancement of rat hepatocellular-altered foci by the liver tumor promoter phenobarbital: evidence that foci are precursors of neoplasms and that the promoter acts on carcinogenic-induced lesions. J. natl Cancer Inst., 61, 1311-1314
14. Peraino, C., Staffeldt, E.F., Haugen, D.A., Lombard, L.S., Stevens, F.J. & Fry, R.J.M. (1980) Effects of varying the dietary concentration of phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res., 40, 3268-3273
15. Takano, T., Tatematsu, M., Hasegawa, R., Imaida, K. & Ito, N. (1980) Dose-response relationship for the promoting effect of phenobarbital on the induction of liver hyperplastic nodules in rats exposed to 2-fluorenylacetamide and carbon tetrachloride. Gann, 71, 580-581
16. Nakanishi, K., Fukushima, S., Hagiwara, A., Tamano, S. & Ito, N. (1982) Organ-specific promoting effects of phenobarbital sodium and sodium saccharin in the induction of liver and urinary bladder tumors in male F344 rats. J. natl Cancer Inst., 68, 497-500
17. Farwell, D.C., Nolan, C.E. & Herbst, E.J. (1978) Liver ornithine decarboxylase during phenobarbital promotion of nitrosamine carcinogenesis. Cancer Lett., 5, 139-144
18. Nishizumi, M. (1979) Effect of phenobarbital, dichlorodiphenyltrichloroethane, and polychlorinated biphenyls on diethylnitrosamine-induced hepatocarcinogenesis. Gann, 70, 835-837
19. Kitagawa, T., Pitot, H.C., Miller, E.C. & Miller, J.A. (1979) Promotion by dietary phenobarbital of hepatocarcinogenesis by 2-methyl-N,N-dimethyl-4-aminoazobenzene in the rat. Cancer Res., 39, 112-115
20. Kitagawa, T., Hirakawa, T., Ishikawa, T., Nemoto, N. & Takayama, S. (1980) Induction of hepatocellular carcinoma in rat liver by initial treatment with benzo[a]pyrene after partial hepatectomy and promotion by phenobarbital. Toxicol. Lett., 6, 167-171
21. Uchida, E. & Hirono, I. (1981) Effect of phenobarbital on the development of neoplastic lesions in the liver of cycasin-treated rats. J. Cancer Res. clin. Oncol., 100, 231-238
22. Shirai, T., Lee, M.-S., Wang, C.Y. & King, C.M. (1981) Effects of partial hepatectomy and dietary phenobarbital in liver and mammary tumorigenesis by two N-hydroxy-N-acylaminobiphenyls in female CD rats. Cancer Res., 41, 2450-2456
23. Moore, M.A., Hacker, H.-J., Kunz, H.W. & Bannasch, P. (1983) Enhancement of NNM-induced carcinogenesis in the rat liver by phenobarbital: a combined morphological and enzyme histochemical approach. Carcinogenesis, 4, 473-479
24. Barbieri, O., Rossi, L., Cabral, J.R.P. & Santi, L. (1983) Carcinogenic effects induced in Wistar rats by combined treatment with technical-grade dichlorodiphenyltrichloroethane and sodium phenobarbital. Cancer Lett., 20, 223-229
25. Hiasa, Y., Kitahori, Y., Ohshima, M., Fujita, T., Yuasa, T., Konishi, N. & Miyashiro, A. (1982) Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine. Carcinogenesis, 3, 1187-1190
26. Moore, M.A., Thamavit, W., Tsuda, H. & Ito, N. (1986) The influence of subsequent dehydroepiandrosterone, diaminopropane, phenobarbital, butylated hydroxyanisole and butylated hydroxytoluene treatment on the development of preneoplastic and neoplastic lesions in the rat initiated with di-hydroxy-di-N-propyl nitrosamine. Cancer Lett., 30, 153-160
27. Tsuda, H., Sakata, T., Shirai, T., Kurata, Y., Tamano, S. & Ito, N. (1984) Modification of N-methyl-N-nitrosourea initiated carcinogenesis in the rat by subsequent treatment with antioxidants, phenobarbital and ethinyl estradiol. Cancer Lett., 24, 19-27
28. IARC Monographs, Suppl. 6, 455-458, 1987
See Also: Toxicological Abbreviations Phenobarbital (IARC Summary & Evaluation, Volume 79, 2001)