For definition of Groups, see Preamble Evaluation.
VOL.: 79 (2001) (p. 91)
Chem. Abstr. Name: 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone
5.1 Exposure data
Propylthiouracil is a thionamide anti-thyroid drug that has been widely used since the 1940s in the treatment of hyperthyroidism. It has been used as a fattening agent in cattle, but this use has been banned.
5.2 Human carcinogenicity studies
No epidemiological data on use of propylthiouracil and cancer were found. However, two analyses were published of one cohort study conducted in the United Kingdom and the USA of the cancer risk of patients, mainly women, with hyperthyroidism who had been treated with anti-thyroid drugs. The earlier analysis showed more malignant thyroid neoplasms in patients receiving these drugs than in those treated with surgery or 131I, but the excess may have been due to closer surveillance of the patients given drugs owing to more frequent use of thyroidectomy. In the later analysis, patients with hyperthyroidism treated only with anti-thyroid drugs had a modest increase in the risk for death from cancer, due chiefly to oral cancer and cancer of the brain. Neither report provided information on the type, quantity or dates of anti-thyroid drug use.
Two case–control studies of cancer of the thyroid showed no significant association with treatment with anti-thyroid medications.
5.3 Animal carcinogenicity data
Although no conventional bioassay of carcinogenicity in rodents has been reported, propylthiouracil has produced tumours in multiple species. In two small studies in mice, oral administration of propylthiouracil produced thyroid follicular-cell carcinomas and tumours of the anterior pituitary. In multiple studies with various strains of rats, propylthiouracil produced thyroid follicular-cell adenomas and carcinomas. In single studies, propylthiouracil produced thyroid follicular-cell adenomas and carcinomas in hamsters and adenomas in guinea-pigs. In initiation–promotion models of thyroid carcinogenesis in rats, propylthiouracil increased the incidence of thyroid follicular-cell tumours initiated by N-methyl-N-nitrosourea or N-nitrosobis(2-hydroxypropyl)amine.
5.4 Other relevant data
The elimination of propylthiouracil in both humans and experimental animals is relatively rapid, and the major metabolic pathway is glucuronidation and excretion in the urine.
The main effect of propylthiouracil in humans and rodents is interference with thyroid peroxidase-mediated iodination of thyroglobulin, which results in decreased plasma concentrations of triiodothyronine and thyroxine and increases in those of thyroid-stimulating hormone, with consequent thyroid follicular-cell proliferation and thyroid growth. This is a plausible mechanism of propylthiouracil-induced tumorigenesis in the thyroid.
Propylthiouracil is not considered to be a human teratogen, although a small percentage of infants whose mothers received the drug during pregnancy developed transient hypothyroidism. Follow-up of small numbers of offspring exposed prenatally did not suggest impairment of intellectual development. Experimental studies on the effects of propylthiouracil focused on the consequences of the induction of hypothyroidism during the early postnatal period on the development and functioning of the brain and reproductive tract. Hyperactivity, auditory deficits and increased sperm production have been observed in rats. The latter outcome is the result of a prolonged period of proliferation of Sertoli cells, and subsequently Leydig cells, in the testes that allows additional spermatogonia in adulthood.
Propylthiouracil has not been adequately tested for gene mutation induction. It did not induce mutations in bacteria, and it was only marginally mutagenic in yeast. Propylthiouracil did not induce chromosomal recombination in insects, DNA strand breaks in rat or human hepatocytes or chromosomal aberrations in a mouse mammary carcinoma-derived cell line. It did not induce chromosomal aberrations in thyroid cells of rats exposed in vivo via the drinking-water.
There is inadequate evidence in humans for the carcinogenicity of propylthiouracil.
There is sufficient evidence in experimental animals for the carcinogenicity of propylthiouracil.
Propylthiouracil is possibly carcinogenic to humans (Group 2B).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 7 (1974); Suppl. 7 (1987)
See Also: Toxicological Abbreviations Propylthiouracil (IARC Summary & Evaluation, Supplement7, 1987) Propylthiouracil (IARC Summary & Evaluation, Volume 7, 1974)