For definition of Groups, see Preamble Evaluation.
VOL.: 66 (1996) (p. 175)
CAS No.:
Chem. Abstr. Name: 5,5-Diphenyl-2,4-imidazolidinedione
CAS No:
Chem. Abstr. Name: 5,5-Diphenyl-2,4-imidazolidinedione, monosodium salt
5.1 Exposure data
Phenytoin, often administered as its sodium salt, has been widely used since the 1930s as an anticonvulsant in the treatment of epilepsy and, to a lesser extent and more recently, in the treatment of certain cardiac arrhythmias.
5.2 Human carcinogenicity data
Many case reports have suggested that there may be a relationship between lymphomas and anticonvulsants, especially phenytoin. In a cohort study in Denmark of epileptic patients exposed to anticonvulsants, including phenytoin, there was an increase in overall cancer risk, attributable to an excess of brain and lung cancer. Nevertheless, brain tumours probably caused the seizure disorder; an evaluation of brain tumour risk over time showed that these tumours were unlikely to be drug-related.
Nested case-control studies based on the Danish cohort investigated in detail the influence of several treatments with anticonvulsants on the risk of cancers of the lung, bladder and liver and non-Hodgkin lymphoma. Anticonvulsant treatment with phenytoin was not associated with lung, bladder or liver cancer. There was an elevated risk for non-Hodgkin lymphoma associated with phenytoin use, but this was not significant.
Two case-control studies investigated the relationship between multiple myeloma and the use of phenytoin, among many other factors. One found no association between phenytoin use and a risk for multiple myeloma. The other study found a nonsignificantly elevated risk associated with the use of phenytoin. The power of both studies to assess an effect of phenytoin was low.
5.3 Animal carcinogenicity data
Phenytoin was tested for carcinogenicity by oral administration in three experiments in mice and in two experiments in rats. It was also tested by perinatal/adult exposure in one study in mice and rats and by intraperitoneal administration in one study in mice.
In one experiment in three strains of female mice, oral administration of the sodium salt of phenytoin was reported to increase the incidence of lymphomas. Oral administration to female mice in another study decreased the incidence of mammary gland adenocarcinomas, leukaemias and polyps of the endometrium; in a further study, the incidence of hepatocellular tumours was reduced in males. Oral administration to rats did not increase the incidence of tumours in two studies.
In the experiment using combinations of adult and perinatal exposure, adult exposure resulted in a dose-dependent increase in the incidence of hepatocellular tumours in female mice. Perinatal treatment followed by adult exposure increased the incidence of hepatocellular tumours in both male and female mice and slightly in male rats. Following intraperitoneal injection of phenytoin into mice, leukaemias and lymphomas were observed.
In one experiment in mice, phenytoin increased the incidence of hepatocellular tumours induced by N-nitrosodiethylamine. In a mouse lung adenoma assay, phenytoin decreased the multiplicity of lung adenomas induced by urethane.
5.4 Other relevant data
Phenytoin is well absorbed in humans. It is eliminated mainly as the glucuronide of the major metabolite, 5-(4'-hydroxyphenyl)-5-phenylhydantoin, which typically accounts for 67-88% of the dose in urine. Several other metabolites are known. The elimination kinetics are non-linear, but an apparent mean half-life of 22 h is a useful guide.
5-(4'-Hydroxyphenyl)-5-phenylhydantoin is the main metabolite in all animal species except dogs (5-(3'-hydroxyphenyl)-5-phenylhydantoin) and cats (the N-glucuronide).
Acute phenytoin intoxication in humans presents usually with cerebellar-vestibular effects such as nystagmus, ataxia, diplopia, vertigo and dysarthria. Chronic administration of phenytoin at therapeutic doses may rarely induce various adverse health effects such as symptoms associated with impairment of the nervous system described above. Gingival overgrowth, sometimes together with increased thickness of the craniofacial bones as well as folic acid deficiency and development of megaloblastic anaemia, are well established adverse effects of the drug. Phenytoin has also been associated with various forms of cutaneous hypersensitivity reactions, sometimes accompanied by lymphadenopathy and benign lymphoid hyperplasia. In rare cases, the histological architecture of the lymph nodes is lost (pseudolymphoma). Phenytoin may also induce a variety of endocrine effects such as reduction of thyroxine concentrations, hypocalcaemia, osteomalacia and hyperglycaemia.
The nervous system appears to be the major target of acute and chronic phenytoin toxicity in experimental animals. In addition, repeated administration of phenytoin induces increased liver and kidney weights, centrilobular hepatic hypertrophy and diverse immunosuppressive effects. Phenytoin may reduce thyroxine concentrations and increase bone thickness in rodents, but gingival hyperplasia has been observed only in cats and monkeys and not in rodents. Phenytoin is an inducer of certain hepatic cytochrome P450 activities in humans and mice. There is evidence for the teratogenicity of phenytoin in humans ingesting 100-800mg per day during the first trimester of gestation. Phenytoin is teratogenic in mice and rats. Animal and a few human studies suggest that neurobehavioural deficits occur at doses which produce no dysmorphic effect.
Phenytoin induced mutations in Salmonella typhimurium in the presence of a metabolic activation system in one study. No mutagenic effect was observed in Drosophila or in mammalian cells in vitro in the absence of an exogenous metabolic system. Aneuploidy was induced in one study in primary mouse embryonic fibroblasts in vitro. Cell transformation was induced in Syrian hamster embryo. A single study showed increased clone sizes of murine macrophages in a host-mediated assay. Phenytoin inhibited gap-junctional intercellular communication. In human lymphocytes in vitro, sister chromatid exchanges were induced in one study and chromosomal aberrations were induced in two of five studies. Aneuploidy was observed in human amnion cells but not in lymphocytes. Phenytoin induced micronuclei in three of five studies in rodents in vivo. Aneuploidy, in one of two studies, aberrant sperm morphology and dominant lethal mutations were induced, but not sister chromatid exchange or chromosomal aberrations.
In general, studies of human lymphocytes in vivo showed no induction of micronuclei, chromosomal aberrations or aneuploidy but an increase of polyploidy was found in one study and of sister chromatid exchange frequencies in three of seven studies. Neither chromosomal aberrations nor aneuploidy were induced in human bone marrow.
The metabolite 5-(4'-hydroxyphenyl)-5-phenylhydantoin was mutagenic in Salmonella typhimurium in the presence of a metabolic activation system; it did not induce micronuclei in mouse bone marrow in vivo.
Mechanistic considerations
Evidence is available to support the conclusion that phenytoin induces liver tumours in mice by a promoting mechanism. The increase in liver weight, centrilobular hypertrophy and pattern of cytochrome P450 induction are similar to those observed with other non-genotoxic mouse liver tumour promoters such as phenobarbital. In addition, the inhibition of cell-cell communication by phenytoin in vitro supports the role of promotion in mouse carcinogenesis.
The metabolic activation of phenytoin to a reactive intermediate has been proposed to account for the teratogenicity and possible genotoxicity of phenytoin. One possible intermediate is an arene oxide, that is hypothesized to result in binding to cellular macromolecules. However, this possibility has not been evaluated definitively, and studies of potential DNA damage in mouse liver or hepatocytes have not been reported. The mechanism of induction of aneuploidy by phenytoin in vitro is unclear, as is its relationship to carcinogenicity in mouse liver.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of phenytoin.
There is sufficient evidence in experimental animals for the carcinogenicity of phenytoin.
Overall evaluation
Phenytoin is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation
Previous evaluation: Suppl. 7 (1987) (p. 319)
Synonyms for Phenytoin
Synonyms for Phenytoin Sodium
See Also:
Toxicological Abbreviations
Phenytoin (PIM 416)