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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Thyrotropic Agents. Lyon (FR): International Agency for Research on Cancer; 2001. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 79.)

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Some Thyrotropic Agents.

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ANTI-THYROID DRUGS

METHIMAZOLE

1. Exposure Data

1.1. Chemical and physical data

1.1.1. Nomenclature
  • Chem. Abstr. Serv. Reg. No.: 60-56-0
  • Deleted CAS Reg. Nos: 4708-61-6; 85916-84-3
  • Chem. Abstr. Name: 1,3-Dihydro-1-methyl-2H-imidazole-2-thione
  • IUPAC Systematic Names: 1-Methylimidazole-2-thiol; 1-methyl-4-imidazoline-2-thione
  • Synonyms: 2-Mercapto-1-methyl-1H-imidazole; 2-mercapto-1-methylimidazole; mercazolylum; 1-methyl-1,3-dihydroimidazole-2-thione; N-methylimidazolethiol; 1-methyl-2-imidazolethiol; 1-methyl-1H-imidazole-2-thiol; 1-methylimidazole2(3H)-thione; 1-methyl-2-mercaptoimidazole; 1-methyl-2-mercapto-1H-imidazole; N-methyl-2-mercaptoimidazole; 1-methyl-2-thioimidazole; thiamazole
1.1.2. Structural and molecular formulae and relative molecular mass
Image 53a
1.1.3. Chemical and physical properties of the pure substance
1.1.4. Technical products and impurities

Methimazole is available as 5- and 10-mg scored tablets (Gennaro, 1995).

Trade names for methimazole include Basolan, Danantizol, Favistan, Frentirox, Mercazole, Metazole, Metibasol, Metothyrine, Strumazol, Tapazole, Thacapzol, Thiamethazole, Thycapzol, Thyrozol and Tirodril (Budavari, 2000; Royal Pharmaceutical Society of Great Britain, 2000; Swiss Pharmaceutical Society, 2000).

1.1.5. Analysis

Several international pharmacopoeias specify infrared absorption spectrophotometry with comparison to standards and colorimetry as the methods for identifying methimazole; titration with sodium hydroxide is used to assay its purity and for its content in pharmaceutical preparations (The Society of Japanese Pharmacopoeia, 1996; AOAC International, 1998; US Pharmacopeial Convention, 1999).

Methods have been reported for the analysis of methimazole in biological fluids (blood, milk, serum, urine), tissues, incubation material and dried animal feed. The methods include capillary zone electrophoresis with ultraviolet detection, micellar electrokinetic chromatography, thin-layer chromatography, high-performance thin-layer chromatography, high-performance liquid chromatography (HPLC) with atmospheric pressure chemical ionization–mass spectrometry, reversed-phase HPLC with ultraviolet detection and gas chromatography with negative-ion chemical ionization–mass spectrometry (Moretti et al., 1986, 1988; Centrich Escarpenter & Rubio Hernández, 1990; Watson et al., 1991; De Brabander et al., 1992; Moretti et al., 1993; Batjoens et al., 1996; Blanchflower et al., 1997; Le Bizec et al., 1997; Buick et al., 1998; Vargas et al., 1998; Esteve-Romero et al., 1999).

1.2. Production

Methimazole can be prepared by reacting aminoacetaldehyde diethyl acetal with methyl isothiocyanate or by reacting thiocyanic acid with N-substituted amino acetals (Aboul-Enein & Al-Badr, 1979; Budavari, 2000).

Information available in 2000 indicated that methimazole was manufactured by three companies in China, two companies in Germany and one company each in Japan, Slovakia and Switzerland (CIS Information Services, 2000a).

Information available in 2000 indicated that methimazole was used in the formulation of pharmaceuticals by five companies in Taiwan, four companies in Germany, three companies in Turkey, two companies each in the Islamic Republic of Iran and Italy and one company each in Argentina, Austria, Belgium, Brazil, Canada, Denmark, Greece, Israel, Mexico, the Netherlands, Peru, the Philippines, Poland, Portugal, the Republic of Korea, Spain, Sweden, Thailand, the Ukraine, the USA and Venezuela (CIS Information Services, 2000b).

1.3. Use

Methimazole is used to control the symptoms of hyperthyroidism associated with Graves disease and to maintain patients in a euthyroid state for several years, until spontaneous remission occurs (American Hospital Formulary Service, 2000).

Methimazole is an anti-thyroid drug, developed in 1949, that is widely used in the treatment of hyperthyroidism. The usual starting dose is 10–30 mg/day, given orally as a single daily dose. Doses as high as 120 mg/day (20 mg every 4 h) may be used in severe thyrotoxicosis (‘thyroid storm’) (Cooper, 1998). Studies have shown better compliance with methimazole than with propylthiouracil (see monograph in this volume), most likely due to the single daily dose of the former (Nicholas et al., 1995). The long duration of action of methimazole makes multiple dosing unnecessary in the vast majority of patients (Roti et al., 1989). There are no intravenous preparations of methimazole, but it has been administered rectally to seriously ill patients who cannot take oral medications. The dose of methimazole is not different for infants, children or the elderly (Cooper, 1998), and it is considered unnecessary to alter the dose for patients with hepatic or renal disease (Cooper, 2000; see also section 4).

Carbimazole, the 3-carbethoxy derivative of methimazole, is converted to methimazole in vivo. It is also in widespread use as an anti-thyroid agent in Europe and Japan. In the USA, propylthiouracil is used as the primary therapy for hyperthyroidism in pregnancy, but methimazole or carbimazole is used as the first treatment in many parts of the world (Masiukiewicz & Burrow, 1999). The doses used are similar to those for non-pregnant women, with an effort to minimize them when possible to avoid fetal hypothyroidism. Methimazole is considered to be safe for use at low doses by lactating women (Azizi, 1996; Azizi et al., 2000).

Anti-thyroid drugs, including methimazole, may be given for several weeks up to 1–2 years. After initiation of therapy, thyroid function improves slowly, returning to normal only by 6–12 weeks of treatment (Okamura et al., 1987). The time that it takes a patient to achieve a euthyroid state depends on a variety of clinical factors, including the severity of the hyperthyroidism at baseline, the size of the thyroid (correlated with intrathyroidal hormonal stores) and the dose of the anti-thyroid drug. Often, as thyroid function improves, the dose of antithyroid drug can be reduced. For example, maintenance doses of methimazole of 2.5–5 mg/day may be adequate to control thyroid function for an extended period. Low doses of anti-thyroid drugs are most successfully used in areas of the world with marginal iodine sufficiency, as high intrathyroidal iodine concentrations would be expected to offset the effects of the drugs (Azizi, 1985).

Methimazole and carbimazole are also used to treat feline hyperthyroidism (Prince, 2000). Methimazole has been used illegally in cattle as a fattening agent (Martínez-Frías et al., 1992).

Methimazole is also used in cyanide-free silver electroplating (Budavari, 2000).

1.4. Occurrence

1.4.1. Occupational exposure

According to the 1981–83 National Occupational Exposure Survey (National Institute for Occupational Safety and Health, 2000) about 700 workers, including pharmacists, health aides and metal-plating machine operators, were potentially exposed to methimazole in the USA.

1.4.2. Environmental occurrence

No data were available to the Working Group.

1.5. Regulations and guidelines

Methimazole is listed in the pharmacopoeias of Italy, Japan, Poland, Taiwan and the USA (The Society of Japanese Pharmacopoeia, 1996; Wang et al., 1998; US Pharmacopeial Convention, 1999; Royal Pharmaceutical Society of Great Britain, 2000) and is also registered for human use in the Netherlands, Portugal, Spain and Sweden (Instituto Nacional de Farmacia e do Medicamento, 2000; Medical Products Agency, 2000; Medicines Evaluation Board Agency, 2000; Spanish Medicines Agency, 2000).

2. Studies of Cancer in Humans

No information was available specifically on methimazole.

2.1. Cohort studies

Dobyns et al. (1974) followed up 34 684 patients treated in England and the USA for hyperthyroidism between 1946 and 1964, 1238 of whom had been treated for at least 1 year with unspecified anti-thyroid drugs. No malignant thyroid neoplasm was found within 1 year of treatment. By 1968, more cases of thyroid neoplasm were found at follow-up among patients initially treated with anti-thyroid drugs (4 malignant tumours and 18 adenomas in 1238 patients) than among those initially treated with 131I (19 malignant tumours and 41 adenomas in 21 714 patients) or (partial) thyroidectomy (4 malignant tumours and 14 adenomas in 11 732 patients). The authors suggested that more neoplasms were found in the drug-treated patients because subsequent thyroidectomy was more frequent in this group (30% of drug-treated patients, as compared with 0.5% of those initially treated with 131I and 1.2% of those treated with primary thyroidectomy), which provided more opportunity for identification of neoplasms. [The Working Group noted that rates could not be calculated because person–years were not provided, and the ages of the groups were not given.]

Ron et al. (1998) updated the report of Dobyns et al. (1974) and followed-up 35 593 patients treated for hyperthyroidism between 1946 and 1964 in 25 clinics in the USA and one in the United Kingdom. By December 1990, about 19% had been lost to follow-up, and 50.5% of the study cohort had died. A total of 1374 patients (1094 women) had been treated with anti-thyroid drugs only, 10 439 (7999 women) with 131I and drugs, 10 381 (8465 women) with thyroidectomy and drugs, 2661 (2235 women) with a combination of the three types of treatment and the remainder by other means. The drugs used during the study period were chiefly thiourea derivatives and iodine compounds. One year or more after the start of the study, the standardized mortality ratio (SMR) in comparison with the general population for the patients treated with anti-thyroid drugs only was 1.3 (95% confidence interval [CI], 1.1–1.6) for deaths from all cancers, which was chiefly due to significantly more deaths from oral cancer (4.2; 95% CI, 1.3–9.7; five cases) and brain tumours (3.7; 95% CI, 1.2–8.6; five cases). The excess risk for death from brain cancer persisted after exclusion of cases prevalent at the time of entry into the study. No deaths from thyroid carcinoma were recorded. The SMR for all cancers was approximately 1.0 in patients treated with 131I or surgery (with or without anti-thyroid drugs), but the SMR for thyroid cancer was fourfold higher (3.9; 95% CI, 2.5–5.9; 24 cases observed) among patients who had been treated with 131I with or without drugs. The authors noted that the group treated with drugs only was small; the type, quantity and dates of drug use were generally not available; and many patients had cancer before entry into the study, suggesting that some, but not all, of the excess could be attributed to the selection of patients with health problems for drug therapy. [The Working Group noted that the expected number of deaths from thyroid carcinomas was not reported, although it would almost certainly have been less than 1.0. Results were given for patients treated only with drugs but not for those given drugs with other treatment.]

2.2. Case–control studies

Ron et al. (1987) conducted a study of 159 cases of thyroid cancer and 285 population controls in Connecticut, USA, between 1978 and 1980. The use of anti-thyroid medications was not associated with an increased risk [relative risks not shown].

In a study carried out in northern Sweden between 1980 and 1989, 180 cases of thyroid cancer and 360 population controls were evaluated (Hallquist et al., 1994). Use of anti-thyroid drugs (two cases and two controls) was associated with a relative risk of 2.0 (95% CI, 0.2–21).

3. Studies of Cancer in Experimental Animals

Studies on the carcinogenicity of anti-thyroid chemicals, including methimazole, in experimental animals have been reviewed (Paynter et al., 1988).

3.1. Oral administration

Mouse: Groups of 78 male and 104 female C3H mice, 2 months of age, received methimazole (pharmaceutical grade) in their drinking-water at a starting dose of 35 mg/L, increased gradually over 26 months to 500 mg/L, when the study was terminated. The control groups comprised 57 male and 81 female untreated mice. No statistically significant increase in the incidence of tumours was seen at any site. An increased incidence of hyperplasia of thyroid gland epithelium in treated mice was described, but the actual incidences were not provided (Jemec, 1970).

Groups of 40 male and 35 female C3H/FIB mice, 2 months of age, received methimazole [purity not specified] at a dose of 250 mg/L of demineralized water in conjunction with a low-iodine pelleted diet (iodine content, 90 µg/kg) for up to 22 months. [The Working Group noted that this concentration of iodine in the diet was 10–30 times lower than that in standard diets used in carcinogenicity studies.] The concentration of methimazole was increased to 500 mg/L when the mice were 4 months old. Groups of 50 male and 50 female mice fed the low-iodine diet served as untreated controls. In addition, groups of 80 male and 108 female mice received methimazole in the drinking-water in conjunction with a high-iodine diet (iodine content, 9–10 mg/kg), the starting dose being 35 mg/L of water, increased gradually over 26 months to 500 mg/L. [The Working Group noted that this concentration of iodine in the diet was 3–10 times that in standard diets used in carcinogenicity studies.] Groups of 236 male and 239 female mice fed the high-iodine diet served as untreated controls. A statistically significant increase (p < 0.01) in the incidence of thyroid follicular-cell adenomas was reported over four periods of observation in the methimazole-treated mice on a low-iodine diet, the incidence being 7/75, including 3/75 in which pulmonary metastases were found. In contrast, the incidences of adenomas in untreated controls on a low-iodine diet or a high-iodine diet and in the methimazole-treated group on a high-iodine diet were 1/150, 0/249 and 0/118, respectively (Jemec, 1977).

Rat: Groups of 25 male and 25 female rats (obtained from Harlan Industries, Cumberland, IN, USA), weighing 86–136 g [age not specified] were given diets containing methimazole (stated as pure) at concentrations of 5, 30 or 180 mg/kg of diet (equivalent to 0.25, 2.5 or 9.0 mg/kg bw per day) for 2 years. The control groups, consisting of 50 males and 50 females, received the diet without methimazole. Survival was poor in the group at the highest dose, the mortality rate being 50% in the first year (compared with < 10% in the other groups), and only 6% were still alive at 2 years, compared with 16–20% in the other groups. The incidence of thyroid follicular-cell tumours was increased at the two higher doses, the incidences for follicular adenoma in males and females combined being 1/55 (2%), 1/8 (13%), 31/55 (56%) and 17/32 (53%) at 0, 5, 30 and 180 mg/kg of diet, respectively [statistical significance not stated], the denominators representing the number of rats surviving when the first tumour was detected in each group. A treatment-related increase in the incidence of follicular adenocarcinoma was found in survivors, the incidences for males and females combined being 1/17 (6%), 5/42 (12%) and 5/24 (21%) at 0, 30 and 180 mg/kg of diet, respectively. The incidence of thyroid follicular hyperplasia was increased in both males and females receiving methimazole at 30 and 180 mg/kg of diet (Owen et al., 1973). [The Working Group noted the inconsistency in the sizes of the groups with thyroid tumours, particularly those with adenomas at 30 mg/kg of diet.]

3.2. Administration with known carcinogens

Rat: In medium-term initiation–promotion bioassays, groups of 20 male Wistar rats were given N-nitrosoethyl-N-hydroxyethylamine as an initiating agent and either trisodium nitrilotriacetate, hydroquinone or potassium dibasic phosphate as the promoting agents, and the effects of methimazole on renal tumour induction were tested. Rats initiated with the nitrosamine underwent nephrectomy of the left kidney and were fed the renal tumour promoters, either alone or in combination with methimazole, in the diet for 20 weeks at concentrations of 1% for trisodium nitrilotriacetate, 2% for hydroquinone, 10% for potassium dibasic phosphate and 300 mg/kg of diet for methimazole. Although methimazole reduced the incidences of renal tubule hyperplasia in each group, it had no effect on the incidence of renal tumours (Konishi et al., 1995).

4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms

4.1. Absorption, distribution, metabolism and excretion

4.1.1. Humans

Jansson et al. (1985) studied the pharmacokinetics of methimazole in healthy, thyrotoxic and hypothyroid persons before and after therapeutic doses for the treatment of euthyroidism. The initial distribution half-time of methimazole was reported to be 0.10–0.23 h, with an elimination half-time of 4.9–5.7 h after intravenous administration. Almost complete oral absorption was observed, with an absolute bioavailability of 93% in fasting persons. There were only minor interindividual variations in the pharmacokinetics, with the exception of one hypothyroid patient who showed a rapid elimination half-time in both the hypothyroid and euthyroid states (2.6 and 2.4 h, respectively). Hengstmann and Hohn (1985) reported elimination half-times of 2–3 h in euthyroid subjects and ∼6 h in hyperthyroid patients. The elimination rate was lower in the hyperthyroid patients than in euthyroid subjects and was not restored when normal thyroid function was achieved. Although renal insufficiency had no effect, patients with hepatic failure had a prolonged elimination half-time of methimazole, the prolongation being proportional to the degree of impairment (Jansson et al., 1985). In hyperthyroid patients receiving carbimazole (1-methyl-2-thio-3-carbethoxyimidazole; see section 1) who then underwent thyroidectomy, the intrathyroidal concentration of methimazole was 518 ng/g of thyroid tissue 3–6 h after administration (Jansson et al., 1983).

The concentrations of methimazole were measured in blood and milk from five lactating women after oral administration of 40 mg of carbimazole, which is rapidly and completely transformed to methimazole. After 1 h, the mean concentrations of methimazole had reached 253 µg/L in serum and 182 µg/L in milk. Methimazole was not bound to protein in the serum, and its concentration in serum was comparable to that in milk. The total amount of methimazole excreted in milk over 8 h was 34 µg (range, 29–47 µg) or about 0.14% of the dose administered (Johansen et al., 1982).

In isolated, perfused, term human placentae, methimazole at doses of 1.5 and 15 µg/mL in either a protein-free perfusate (low dose only) or a perfusate containing 40 g/L bovine albumin readily crossed the placenta and reached equilibrium within 2 h. The transfer of methimazole was similar to that of propylthiouracil (see monograph in this volume; Mortimer et al., 1997).

4.1.2. Experimental systems

In studies in which radiolabelled methimazole was administered to Sprague-Dawley rats intravenously, intraperitoneally or orally (the drug was reported to be completely absorbed after oral administration), about 5% was found to be bound to plasma proteins, and it seemed to be ubiquitously distributed to all tissues studied, although Pittman et al. (1971) reported that the thyroid and adrenal glands had the highest organ:plasma ratios. Approximately 10% of the administered radiolabel appeared in the bile, whereas 77–95% was excreted into the urine, with negligible amounts in the faeces, suggesting enterohepatic circulation. The half-time of urinary excretion of radiolabel was 5–7 h, regardless of the route of administration. Of the total radiolabel excreted in the urine, 14–21% was associated with unchanged drug. The major urinary and biliary metabolite was methimazole glucuronide (36–48%), and three other unidentified metabolites were found in the bile (Sitar & Thornhill, 1973; Skellern et al., 1973; Skellern & Steer, 1981).

Lee and Neal (1978) demonstrated that incubation in vitro of methimazole with rat hepatic microsomes led to the formation of 3-methyl-2-thiohydantoin and N-methylimidazole. They also showed that radiolabelled methimazole bound to microsomal macromolecules and that this binding was stimulated by NADPH. The cytochrome P450 and flavin-containing monooxygenase systems of rat hepatic microsomes have been implicated in these reactions (see section 4.2.2).

4.1.3. Comparison of animals and humans

In humans and rodents, methimazole is readily absorbed and rapidly excreted with a half-time of 5 h. In rats, glucuronidation is the main metabolic pathway; less is known about the metabolism of methimazole in humans.

4.2. Toxic effects

4.2.1. Humans
(a) Effects on thyroid function at therapeutic doses

Methimazole is commonly used to treat hyperthyroidism. It inhibits intrathyroidal synthesis of thyroid hormones by interfering with thyroid peroxidase-mediated iodine utilization. As a result, the concentrations of thyroxine (T4) and triiodothyronine (T3) in serum are decreased (Cooper, 2000). In some studies, hyperthyroid patients became hypothyroid if the dose of methimazole was not monitored carefully. In one study, 100% of patients became hypothyroid within 12 weeks while taking 40 mg/day (Kallner et al., 1996).

(b) Other studies in humans

Most of the toxic effects of methimazole are considered to be allergenic, including fever, skin rashes and arthralgia. Agranulocytosis is the most significant major side-effect, occurring in 4 of 13 patients investigated in one study. Cholestatic jaundice is a rare severe side-effect (Vitug & Goldman, 1985). The side-effects of methimazole appear to be dose-related (Cooper, 1999). In a study of the toxic effects of methimazole in hyperthyroid patients receiving high daily doses of 40–120 mg, the major effects were agranulocytosis, granulocytopenia and abnormal liver function in 3% of patients, whereas 13% showed minor effects such as arthralgia, skin rash and gastric intolerance (Romaldini et al., 1991). Other reports also indicate that rashes and agranulocytosis are the major side-effects (Wiberg & Nuttall, 1972; Van der Klauw et al., 1999). At high doses (up to 120 mg/day), the incidence (32%) and severity of side-effects were increased (Wiberg & Nuttall, 1972; Meyer-Gessner et al., 1994).

Methimazole therapy induced changes in plasma lipid peroxidation and the antioxidant system in hyperthyroid and euthyroid patients. Lipid peroxide plasma concentrations were decreased while ascorbic acid and vitamin E levels were significantly increased in euthyroid patients in comparison with hyperthyroid patients. Plasma glutathione peroxidase activity was increased and glutathione transferase activity was significantly decreased after euthyroidism was sustained with methimazole therapy (Ademoglu et al., 1998).

Thyroglobulin mRNA levels and accumulation of thyroglobulin in the culture medium were enhanced by addition of methimazole to the Fischer rat thyroid cell line 5. The effect on Tg gene expression was independent of thyroid-stimulating hormone (TSH) or insulin concentrations, and methimazole did not alter TSH-induced cAMP production. Both iodide and cycloheximide (a protein synthesis inhibitor) inhibited the stimulatory effects of methimazole on protein synthesis (Leer et al., 1991).

4.2.2. Experimental systems

Male marmosets (Callithrix jacchus) were given methimazole at an oral dose of 10 or 30 mg/kg bw per day for 4 weeks. Marked hypertropy of follicular epithelial cells was observed, with a significant decrease in the plasma T4 concentration. Hypertrophied epithelial cells were filled with dilated rough endoplasmic reticulum and reabsorbed intracellular colloid, with vacuoles that were positive to anti-T4 immunostaining (Kurata et al., 2000).

Hood et al. (1999) examined the effect in rats of various concentrations of methimazole in the diet. The concentrations of total and free T4 were reduced by more than 95% after 21 days of treatment with increasing dietary concentrations of 30, 100, 300 and 1000 ppm (mg/kg), and those of total and free T3 were reduced by 60%. Feeding rats with diets containing 30 ppm (mg/kg) methimazole for 21 days resulted in a 5.6-fold increase in TSH, a 14-fold increase in thyroid follicular-cell proliferation and a twofold increase in thyroid weight. The increases in thyroid weight and follicular-cell proliferation were significantly correlated with the increase in TSH.

Administration of methimazole at a concentration of 0.05% in the drinking-water for 32 days to male Sprague-Dawley rats decreased the serum concentrations of T3 (by 80%) and T4 (by 90%) and also decreased the rate of body-weight gain, colonic temperature, systolic blood pressure and heart rate when compared with vehicle-treated rats (Bhargava et al., 1988). Methimazole given in combination with dl-buthionine sulfoximine, an inhibitor of glutathione synthesis, caused centrilobular necrosis of hepatocytes and increased hepatic serum alanine aminotransferase activity in male ICR mice. Methimazole given to mice with normal levels of glutathione produced only a marginal increase in serum alanine aminotransferase activity and was not hepatoxic. Pretreatment with hepatic cytochrome P450 monooxygenase inhibitors prevented or at least greatly reduced the hepatotoxicity of methimazole in combination with dl-buthionine sulfoximine. Competitive substrates for flavin-containing monooxygenases also eliminated the hepatotoxicity of the two compounds in combination, indicating that methimazole is metabolized to an active hepatotoxicant by both cytochrome P450 monooxygenases and flavin-containing monooxygenases, and that inadequate rates of detoxication of the resulting metabolite(s) are responsible for the hepatotoxicity in glutathione-depleted mice (Mizutani et al., 1999).

Methimazole was toxic to the olfactory system in Long-Evans rats given a single intraperitoneal dose of ≥ 25 mg/kg bw or an oral dose of ≥ 50 mg/kg bw. A 300-mg/kg bw intraperitoneal dose resulted in almost complete destruction of the olfactory epithelium (Genter et al., 1995). Bergman and Brittebo (1999) reported that [3H]methimazole given to NMRI mice by intravenous injection showed selective covalent binding to Bowman glands in the olfactory mucosa, bronchial epithelium in the lungs and centrilobular parts of the liver. Extensive lesions of the olfactory mucosa were observed after two consecutive intraperitoneal doses of methimazole, but these were efficiently repaired within 3 months. Pretreatment with T4 did not protect against toxicity, but pretreatment with metyrapone (a cytochrome P450 inhibitor) completely prevented methimazole-induced toxicity and covalent binding in the olfactory mucosa and bulb.

4.3. Reproductive and developmental effects

4.3.1. Humans

Pregnancy outcomes after use of methimazole during gestation have been reviewed. No differences in the rates of malformations were seen in the infants of hyperthyroid mothers who had and had not taken methimazole; however, 17 cases of aplasia cutis congenita were found in the offspring of women who had used methimazole. The authors estimated an expected incidence of 9.4 cases on the basis of the overall incidence of hyperthyroidism during pregnancy, the prevalence of methimazole use by hyperthyroid patients and the background incidence of the effect. They also reported that no signs of intellectual impairment were found in four studies involving 101 children whose mothers had undergone thioamide therapy (Mandel et al., 1994). Other cases of aplasia cutis have been reported in infants whose mothers were treated with methimazole during pregnancy (Sargent et al., 1994; Vogt et al., 1995). Martínez-Frías et al. (1992) suggested that an increase in the incidence of aplasia cutis noted between 1980 and 1990 in the Spanish Collaborative Study of Congenital Malformations might have been due to illicit use of methimazole in animal feed, although no actual exposure was confirmed in this report. In contrast, no significant increase in the overall incidence of congenital malformations was noted in 36 women on methimazole therapy, and, in particular, no scalp defects were observed in the exposed infants (Wing et al., 1994). Similarly, a review of nearly 50 000 pregnancies in the Netherlands found no association between exposure to methimazole and defects of the skin or scalp (Van Dijke et al., 1987). An association between use of methimazole and choanal and oesophageal atresia has also been reported (summarized by Clementi et al., 1999).

Thyroid status at delivery was evaluated in the infants of 43 women who had been treated with methimazole for Graves disease for at least 4 weeks during pregnancy and compared with that of the infants of 32 women with no history of thyroid problems. The doses ranged from 2.5 to 20 mg/day. No difference was found in the mean concentration of free T4 or TSH in the cord blood of infants in the two groups. A similar lack of effect was seen in 34 women treated with propylthiouracil (see monograph in this volume; Momotani et al., 1997).

4.3.2. Experimental systems

Postnatal neurological development was evaluated in the offspring of groups of eight Sprague-Dawley rats given drinking-water containing methimazole at a concentration of 0 or 0.1 g/L from day 17 of gestation to postnatal day 10. The growth of offspring was reduced relative to that of controls after postnatal day 2, and they showed significant delays in acquisition of the surface-righting response (at 14 days vs 7 days in controls), auditory startle reflex (at 18 vs 12 days) and eye opening (at 17 vs 15 days). They also showed a significant reduction in locomotor activity in a 10-min open-field test at 21 days (Comer & Norton, 1982). In a study of the same design, 6-week-old, 4-month-old and 6-month-old rat offspring showed a pattern of relative decreases in locomotor activity in a residential maze, the result of a lack of habituation and a lack of a diurnal motor pattern. The treated offspring also had an asymmetric walking gait and alterations in exploratory patterns in a radial-arm maze. The two sexes were affected equally in all measures (Comer & Norton, 1985).

In groups of three Wistar rats given drinking-water containing methimazole at a concentration of 0 or 0.025% from day 8 of gestation, the total serum T3 and T4 concentrations were significantly reduced on day 18 of gestation, but fetal body weights were not affected nor were there any changes in the histological appearance of the testes. Treatment of offspring with 0 or 0.05% methimazole in the drinking-water from birth onwards significantly reduced the total serum concentrations of T3 and T4 at 21 and 50 days of age and reduced both body-weight gain and testis weight. [These rats were not old enough for the enlarged testes and enhanced sperm production observed in rats similarly treated with propylthiouracil (see monograph in this volume) to be seen]. Serum follicular-stimulating hormone and luteinizing hormone concentrations were reduced at 35 and 50 days of age. The hypothyroid rats showed delayed maturation of the testes, as seen by a decrease in the diameter of the seminiferous tubules and a reduction in the number of germ cells per cross-section. Sertoli cells also showed retarded development. With the exception of the reduction in total T4 concentration, the effects were reversible by concomitant administration of l-T3 (100 µg/kg bw every other day) (Francavilla et al., 1991).

The teratogenic potential of methimazole was compared with that of ethylenethiourea (see monograph in this volume) in rat embryo cultures. Exposure of 9.5-day-old Wistar rat embryos to methimazole at a concentration of 100 µmol/L for 48 h did not affect the morphology of the embryos, but at 500 µmol/L the mean apparent embryonic age and somite number were statistically significantly lower than those of controls. At higher concentrations (1, 2 and 5 mmol/L), the yolk-sac diameter and crown–rump length were also lower (p < 0.05) than those of controls. While some similarities in embryonic responses were noted, the failure of closure of the cranial region in many embryos exposed to methimazole was not seen in embryos exposed to ethylenethiourea, and other effects seen in ethylenethiourea-exposed embryos were not seen in those exposed to methimazole (Stanisstreet et al., 1990).

The effect of methimazole-induced hypothyroidism during the neonatal period on testicular development was studied in Sprague-Dawley rats. Dams were given 0 or 0.025% methimazole in the drinking-water for 25 days from the day of parturition. Only male offspring were maintained in the litters [number of litters per group not specified]. Serum thyroid hormone concentrations were depressed at 25 days of age, but were normal by day 45. Body-weight gain was reduced early in life and remained 11% lower than that of controls at 90 days of age. At 90 days of age, the testis weights were increased by 18%, and daily sperm production was slightly increased. The effects were largely equivalent to those obtained after exposure to 0.004% propylthiouracil during the same neonatal period (Cooke et al., 1993).

Postnatal development of Swiss Webster mice was examined after administration of 0 (10 dams) or 0.1 g/L (12 dams) methimazole in the drinking-water from day 16 of gestation through day 10 of lactation. There was no effect on litter size at birth. Body weights were reduced through young adulthood, after which the effect was no longer significant. Developmental milestones (incisor eruption, eye opening, vaginal opening, testis descent) were unaffected. Surface–righting time (tested on days 7–11), negative geotaxis (tested on days 6, 8 and 10) and swimming ontogeny (tested on days 4–20) were affected by exposure. There were no effects on rotarod performance on day 52 or on brain weights on day 120 (Rice et al., 1987).

Neurological effects were studied in Fischer 344 rats exposed to methimazole in the drinking-water from gestational day 17 through lactational day 10 at a dose of 0, 0.01, 0.03 or 0.1 g/L, with approximately 12 litters per group. A number of indicators of neurological maturation, behaviour, thermoregulation, neurophysiology and morphology were measured at various ages. Pup weight (day 4), age at incisor eruption, thyroid histopathology (day 11), flash-evoked potential (day 14) and somatosensory-evoked potentials in the 60–120-Hz range (day 90) were significantly altered at all doses. Thermoregulation (day 12) was reduced and kidney weights increased (day 11) at concentrations ≥ 0.03 g/L. Body weight (day 12) and auditory brainstem responses (day 90) were affected at the highest concentration. Body weights on day 14 were normal in all treated groups (Albee et al., 1989).

4.4. Effects on enzyme induction or inhibition and gene expression

No data were available to the Working Group.

4.5. Genetic and related effects

4.5.1. Humans

No data were available to the Working Group.

4.5.2. Experimental systems (see Table 1 for references)
Table 1. Genetic and related effects of methimazole.

Table 1

Genetic and related effects of methimazole.

Methimazole did not induce forward mutation in a fluctuation test with Klebsiella pneumoniae.

Methimazole induced chromosomal aberrations in a cell line derived from mouse mammary carcinoma and inhibited cell-to-cell communication in a primary culture of rat thyrocytes. Incubation of methimazole-treated thyrocytes from Sprague-Dawley rats with TSH did not affect the inhibitory effects of methimazole on gap-junctional intercellular communication.

No chromosomal aberrations were induced in bone-marrow cells, spermatogonia or primary spermatocytes of mice treated subcutaneously with methimazole for up to 5 days. The bone-marrow cells from these mice did not contain micronuclei. The frequency of sister chromatid exchange was increased in T lymphocytes of mice given 0.1% methimazole in the drinking-water for 2–6 weeks.

Subcutaneous injection of methimazole did not induce dominant lethal mutations in male mice.

4.6. Mechanistic considerations

Methimazole belongs to a class of drugs used in the treatment of hyperthyroidism, which act by interfering with the functioning of thyroid peroxidase. The mode of action in experimental animals is inhibition of thyroid peroxidase, which decreases thyroid hormone production and increases cell proliferation by increasing the secretion of TSH. This is the probable basis of the tumorigenic activity of methimazole for the thyroid in experimental animals.

Methimazole was not adequately tested to support a conclusion regarding its classification as a genotoxin or a non-genotoxin. It inhibited gap-junctional intercellular communication in primary rat hepatocytes in vitro.

5. Summary of Data Reported and Evaluation

5.1. Exposure data

Methimazole is an anti-thyroid drug, introduced in 1949, which is widely used 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 methimazole 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

Methimazole was tested by oral administration in two limited studies in mice and in one study in rats. In one study in mice, it increased the incidence of thyroid follicular-cell adenomas but only in conjunction with a low-iodine diet. It produced thyroid follicular-cell adenomas and carcinomas in the study in rats.

5.4. Other relevant data

In humans and rodents, methimazole is readily absorbed and rapidly excreted. In rats, glucuronidation is the major metabolic pathway; less is known about its metabolism in humans.

The mode of action of methimazole in the thyroid in experimental animals involves inhibition of thyroid peroxidase, which decreases thyroid hormone production and increases proliferation by increasing the secretion of thyroid-stimulating hormone. This is the probable basis for the tumorigenic activity of methimazole for the thyroid in experimental animals.

While the overall incidence of malformations in the infants of women given methimazole during pregnancy does not appear to be elevated, there is equivocal evidence for an association with the occurrence of aplasia cutis, a skin defect. Most of the studies in experimental animals focused on the consequences of hypothyroidism subsequent to perinatal or early postnatal exposure of rats to methimazole; effects on adult neurobehavioural and testicular function were found. Neurobehavioural effects have also been reported in mice exposed perinatally to methimazole.

Methimazole has not been adequately tested for its ability to induce gene mutations. It induced chromosomal aberrations in mammalian cells in vitro, but the results of studies of its ability to induce chromosomal damage in vivo were mainly negative.

5.5. Evaluation

There is inadequate evidence in humans for the carcinogenicity of methimazole.

There is limited evidence in experimental animals for the carcinogenicity of methimazole.

Overall evaluation

Methimazole is not classifiable as to its carcinogenicity to humans (Group 3).

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METHYLTHIOURACIL

This substance was considered by previous working groups, in 1974 (IARC, 1974) and 1987 (IARC, 1987). Since that time, new data have become available, and these have been incorporated into the monograph and taken into consideration in the present evaluation.

1. Exposure Data

1.1. Chemical and physical data

1.1.1. Nomenclature
  • Chem. Abstr. Serv. Reg. No.: 56-04-2
  • Deleted CAS Reg. Nos: 1123-10-0; 31909-18-9; 91795-77-6
  • Chem. Abstr. Name: 2,3-Dihydro-6-methyl-2-thioxo-4(1H)-pyrimidinone
  • IUPAC Systematic Name: 6-Methyl-2-thiouracil
  • Synonyms: 4-Hydroxy-2-mercapto-6-methylpyrimidine; 4-hydroxy-6-methyl-2-mercaptopyrimidine; 2-mercapto-4-methyl-6-hydroxypyrimidine; 2-mercapto-6-methyl-4-pyrimidinol; 2-mercapto-6-methylpyrimidin-4-one; 6-methyl-2-mercaptouracil; 4-methyl-2-thiouracil; MTU; 2-thio-6-methyluracil; 6-thio-4-methyluracil
1.1.2. Structural and molecular formulae and relative molecular mass
Image 75a
1.1.3. Chemical and physical properties of the pure substance
1.1.4. Technical products and impurities

Trade names for methylthiouracil include Alkiron, Antibason, Basecil, Basethyrin, Metacil, Methacil, Methiacil, Methicil, Methiocil, Muracil, Prostrumyl, Strumacil, Thimecil, Thiothymin, Thyreonorm, Thyreostat, Thyreostat I, Tiomeracil and Tiorale M.

1.1.5. Analysis

Methods have been reported for the analysis of methylthiouracil in biological fluids (blood, milk, serum, urine), tissues, dried animal feed and feed additives. The methods include capillary zone electrophoresis with ultraviolet detection, micellar electrokinetic chromatography, thin-layer chromatography, high-performance thin-layer chromatography, high-performance liquid chromatography (HPLC) with atmospheric pressure chemical ionization–mass spectrometry, reversed-phase HPLC with ultraviolet and electrochemical detection and gas chromatography with mass spectrometry (Saldaña Monllor et al., 1980; Moretti et al., 1986; Hooijerink & De Ruig, 1987; Moretti et al., 1988; Centrich Escarpenter & Rubio Hernández, 1990; De Brabander et al., 1992; Moretti et al., 1993; Batjoens et al., 1996; Krivánková et al., 1996; Blanchflower et al., 1997; Le Bizec et al., 1997; Yu et al., 1997; Buick et al., 1998; Vargas et al., 1998; Esteve-Romero et al., 1999).

1.2. Production

Methylthiouracil can be made by condensation of ethyl acetoacetate with thiourea (IARC, 1974)

Information available in 2000 indicated that methylthiouracil was manufactured by two companies each in China and Germany and one company each in Austria, Italy and Japan (CIS Information Services, 2000a; Herbrand, 2000).

Information available in 2000 indicated that methylthiouracil was used in the formulation of pharmaceutical drugs by one company in Poland (CIS Information Services, 2000b).

1.3. Use

Methylthiouracil was introduced in the mid-1940s, at the same time as propylthiouracil, as a thionamide anti-thyroid drug for the treatment of hyperthyroidism. The usual dose is 200 mg/day in two to four equally spaced doses. Methylthiouracil is no longer in clinical use in most countries, although it may be used to a limited degree in some eastern European countries. It has not been registered for human use since 1958 in Sweden, 1986 in the United Kingdom and 1988 in the Netherlands (Medical Products Agency, 2000; Medicines Control Agency, 2000; Medicines Evaluation Board Agency, 2000). A MEDLINE search revealed no references to use of methylthiouracil since 1987 (Junik et al., 1987). This may be related to the higher rate of adverse reactions than with propylthiouracil or methimazole (see monographs in this volume) (Van der Laan & Storrie, 1955).

1.4. Occurrence

1.4.1. Occupational exposure

No data were available to the Working Group.

1.4.2. Environmental occurrence

No data were available to the Working Group.

1.5. Regulations and guidelines

Methylthiouracil is listed in the current pharmacopoeias of Austria, Poland and Switzerland. It was previously listed in the pharmacopoeias of the former East Germany, Italy, Japan (1976), the United Kingdom (1973) and the USA (XXI) (Royal Pharmaceutical Society of Great Britain, 2000; Swiss Pharmaceutical Society, 2000). It was also formerly listed in the International Pharmacopoeia (II).

2. Studies of Cancer in Humans

No information was available specifically on methylthiouracil.

2.1. Cohort studies

Dobyns et al. (1974) followed up 34 684 patients treated in England and the USA for hyperthyroidism between 1946 and 1964, 1238 of whom had been treated for at least 1 year with unspecified anti-thyroid drugs. No malignant thyroid neoplasm was found within 1 year of treatment. By 1968, more cases of thyroid neoplasm were found at follow-up among patients initially treated with anti-thyroid drugs (4 malignant tumours and 18 adenomas in 1238 patients) than among those initially treated with 131I (19 malignant tumours and 41 adenomas in 21 714 patients) or (partial) thyroidectomy (4 malignant tumours and 14 adenomas in 11 732 patients). The authors suggested that more neoplasms were found in the drug-treated patients because subsequent thyroidectomy was more frequent in this group (30% of drug-treated patients, as compared with 0.5% of those initially treated with 131I and 1.2% of those treated with primary thyroidectomy), which provided more opportunity for identification of neoplasms. [The Working Group noted that rates could not be calculated because person–years were not provided, and the ages of the groups were not given.]

Ron et al. (1998) updated the report of Dobyns et al. (1974) and followed-up 35 593 patients treated for hyperthyroidism between 1946 and 1964 in 25 clinics in the USA and one in the United Kingdom. By December 1990, about 19% had been lost to follow-up, and 50.5% of the study cohort had died. A total of 1374 patients (1094 women) had been treated with anti-thyroid drugs only, 10 439 (7999 women) with 131I and drugs, 10 381 (8465 women) with thyroidectomy and drugs, 2661 (2235 women) with a combination of the three types of treatment and the remainder by other means. The drugs used during the study period were chiefly thiourea derivatives and iodine compounds. One year or more after the start of the study, the standardized mortality ratio (SMR) in comparison with the general population for the patients treated with anti-thyroid drugs only was 1.3 (95% confidence interval [CI], 1.1–1.6) for deaths from all cancers, which was chiefly due to significantly more deaths from oral cancer (4.2; 95% CI, 1.3–9.7; five cases) and brain tumours (3.7; 95% CI, 1.2–8.6; five cases). The excess risk for death from brain cancer persisted after exclusion of cases prevalent at the time of entry into the study. No deaths from thyroid carcinoma were recorded. The SMR for all cancers was approximately 1.0 in patients treated with 131I or surgery (with or without anti-thyroid drugs), but the SMR for thyroid cancer was fourfold higher (3.9; 95% CI, 2.5–5.9; 24 cases observed) among patients who had been treated with 131I with or without drugs. The authors noted that the group treated with drugs only was small; the type, quantity and dates of drug use were generally not available; and many patients had cancer before entry into the study, suggesting that some, but not all, of the excess could be attributed to the selection of patients with health problems for drug therapy. [The Working Group noted that the expected number of deaths from thyroid carcinomas was not reported, although it would almost certainly have been less than 1.0. Results were given separately for patients treated only with drugs and not for those given drugs with other treatment.]

2.2. Case–control studies

Ron et al. (1987) conducted a study of 159 cases of thyroid cancer and 285 population controls in Connecticut, USA, between 1978 and 1980. The use of antithyroid medications was not associated with an increased risk [relative risks not shown].

In a study carried out in northern Sweden between 1980 and 1989, 180 cases of thyroid cancer and 360 population controls were evaluated (Hallquist et al., 1994). Use of anti-thyroid drugs (two cases and two controls) was associated with a relative risk of 2.0 (95% CI, 0.2–21).

3. Studies of Cancer in Experimental Animals

Methylthiouracil was evaluated in a previous monograph (IARC, 1974). Although there have been several new studies on the carcinogenicity of methylthiouracil in animals, no conventional bioassays have been reported. The summaries of the most relevant studies from the previous monograph are either repeated here or the studies are analysed in greater depth. Studies on the carcinogenicity of anti-thyroid chemicals, including methylthiouracil, in experimental animals have been reviewed (Doniach, 1970; Christov & Raichev, 1972a).

3.1. Oral administration

Mouse: In a study published since the previous evaluation, groups of 94 male and 82 female C3H/FIB mice, 2 months of age, were given methylthiouracil [purity not specified] in their drinking-water at a concentration of 0 or 1000 mg/L in conjunction with an iodine-rich diet (9–10 mg/kg). A group of 236 male and 239 female mice served as untreated controls on an iodine-rich diet. Another group of 42 males and 53 females of the same strain and age received methylthiouracil mixed into pelleted diet at a concentration of 2000 mg/kg, which was increased to 5000 mg/kg of diet when they were 4 months of age, in conjunction with an iodine-poor diet (90 µg/kg). Groups of 50 males and 50 females served as untreated controls on iodine-poor diet. Groups of animals were killed after 6–22 months of treatment. Methylthiouracil caused a statistically significant increase (p < 0.01) in the incidence of thyroid adenomas in mice on the iodine-poor diet (23/75, including 13/75 with pulmonary metastases). In contrast, the incidences of thyroid adenoma were 1/150 in control mice on the iodine-poor diet, 0/249 in control mice on the iodine-rich diet and 2/167 in methylthiouraciltreated mice on the iodine-rich diet. Methylthiouracil also produced hepatomas in 28/75 mice on the iodine-poor diet (p < 0.01), in 6/167 mice on the iodine-rich diet, in 2/150 control mice on the iodine-poor diet and in 6/249 control mice on the iodine-rich diet. All of these incidences refer to pooled males and females (Jemec, 1977).

Rat: Groups of female Long-Evans rats, approximately 9 months of age, were given methylthiouracil [route not specified clearly but presumed to be dietary] at a dose of 0 (31 rats at start) or 2.5 mg/rat per day (34 rats at start) in combination with a low-iodine diet (average, 100–150 µg/kg of diet) for 24–33 months. Administration of methylthiouracil resulted in thyroid hyperplasia in 22/24 rats, ‘nodular thyroid changes’ in 15/24 rats and thyroid carcinoma in 8/24 rats examined. In the group receiving the low-iodine diet only, 1/31 had thyroid hyperplasia, 3/31 had nodular changes and 0/31 had thyroid carcinoma (Field et al., 1959). [The Working Group considered the nodular changes to be adenomas.]

In a study published since the previous evaluation, two groups of inbred Wistar/FIB rats (39 and 57 animals at start), 2 months of age, were given methylthiouracil [purity not specified] in their drinking-water at a concentration of 0 (control) or 0.1% [length of exposure not specified]. A third group (43 rats at start) was hypophysectomized, given methylthiouracil (0.1%) 5–6 days after the operation and killed 7–8 months later. The author reported that the average age at death did not differ significantly in the three groups. Thyroid tumours occurred in 16/57 intact rats given methylthiouracil, 0/39 of the controls and 0/32 hypophysectomized rats receiving methylthiouracil. Of the 16 tumour-bearing rats given methylthiouracil only, nine had thyroid adenomas and seven had carcinomas metastasizing to the lungs. As part of a second experiment, groups of Wistar/FIB rats [initial numbers and sex not specified], 2 months of age, were given methylthiouracil [purity not specified] in the drinking-water at a concentration of 0 (control) or 0.25% for 2 years. Methylthiouracil induced thyroid adenomas in 11/30 rats (five with pulmonary nodules), whereas none were seen in 33 controls (Jemec, 1980).

In another study published since the previous evaluation, groups of white random-bred rats, 3 months of age, were given methylthiouracil [purity not specified] in the drinking-water at a concentration of 0 or 0.1% until natural death or were killed when moribund. Methylthiouracil produced thyroid tumours in 39/58 treated rats (38 adenomas, one carcinoma; p < 0.01) and produced thyroid adenomas in 3/100 controls (Alexandrov et al., 1989).

Hamster: Groups of hamsters, 3 months of age, were given methylthiouracil [purity not specified] in the drinking-water at a concentration of 0 (control) or 0.2%. Between four and 12 animals in each group were killed at regular intervals after 2–12 months of exposure. The first thyroid adenoma was recorded after 5 months of treatment with methylthiouracil; the total incidence of animals with thyroid adenomas by the end of the experiment was 20/77 treated hamsters and 0/37 controls (Christov & Raichev, 1972b).

3.2. Administration with known carcinogens

Rat: Groups of Debrecen or CB albino rats of each sex [initial numbers unspecified], 2.5–4 months of age, were given 2-acetylaminofluorene intragastrically at a dose of 2.5 mg/rat three times a week for 6 weeks and methylthiouracil [purity not specified] in the drinking-water at a concentration of 0.01% for a total experimental period of 71 weeks. Combined exposure to 2-acetylaminofluorene, methylthiouracil and a low-iodine diet produced thyroid adenomas in 100% of the rats that lived for 5 months or longer [number not stated], compared with 0/30 rats treated with 2-acetylaminofluorene alone and 1/25 rats treated with methylthiouracil alone (Lapis & Vekerdi, 1962).

In a study published since the previous evaluation, 75 female Wistar rats weighing 150 g [age not specified] were given a single oral dose of 40 mg/kg bw N-methyl-N-nitrosourea (MNU) on 3 consecutive days followed 4 weeks later by methylthiouracil [purity not specified] in the drinking-water at a concentration of 0.1% up to week 60 of the experiment. Thyroid tumours were observed from week 16 and carcinomas from week 24. After 30 weeks, 13 rats had tumours with metastases to the lungs (Schäffer & Müller, 1980). [The Working Group noted that the numbers of rats sampled at various times were not given, nor was the incidence, but the latter was inferred to be 100%.]

In a multigeneration study published since the previous evaluation, groups of white random-bred female rats [initial numbers and age not specified] received an intraperitoneal injection of MNU at 20 mg/kg bw in 0.9% saline on day 21 of gestation. Groups of rats of the F1 generation received either no further treatment or methylthiouracil in their drinking-water at a concentration of 0.1% (about 100 mg/kg bw per day) for life. Two additional groups of rats with no transplacental exposure to MNU received either methylthiouracil alone as above or no treatment (control group). Methylthiouracil caused a statistically significant increase (p < 0.01) in the incidence of MNU-induced thyroid tumours, from 4/100 with MNU alone to 33/43 with MNU plus methylthiouracil, but decreased (p < 0.01) the incidence of MNU-induced kidney and nervous system tumours. The incidences of thyroid tumours in rats given methylthiouracil are reported in section 3.1.2 (Alexandrov et al., 1989).

4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms

4.1. Absorption, distribution, metabolism and excretion

4.1.1. Humans

No data were available to the Working Group.

4.1.2. Experimental systems

After intravenous injection of a single dose of 5 mg methylthiouracil, 84–90% of the dose could be recovered from the carcasses of animals killed after 1 min and 55–60% from the carcasses of animals killed after 3 h. At 3 h, the concentration of methylthiouracil in the thyroid was approximately 1 mg/g of tissue (Williams & Kay, 1947).

Methylthiouracil crossed the placental barrier and was excreted in the milk of lactating rats (Napalkov & Alexandrov, 1968).

After male Sprague-Dawley rats were given an intraperitoneal injection of [35S]methylthiouracil in alkaline saline (pH 8.0), accumulation of radiolabel was observed in the thyroid, with a thyroid:plasma ratio of 43 (Marchant et al., 1972).

4.2. Toxic effects

4.2.1. Humans

Use of methylthiouracil is associated with a high frequency of agranulocytosis (Westwick et al., 1972). Use of this drug by a 21-year-old woman led to a bullous haemorrhagic rash (Cox et al., 1985).

4.2.2. Experimental systems

Methylthiouracil (0.03%) given in the drinking-water to male Wistar rats had increased the plasma concentrations of thyroid-stimulating hormone by 1 week after the start of the treatment; however, the plasma concentrations of triiodothyronine and thyroxine were markedly decreased by 2 weeks (Tohei et al., 1997).

Male Wistar/Holtzman rats given an intraperitoneal injection of 40 mg of methylthiouracil showed acute increases in the secretion of thyroid-stimulating hormone and interference with the recycling of iodide (Onaya et al., 1973).

Male and female C57BL mice were given diets containing methylthiouracil at a concentration of 0.3 or 0.5% ad libitum for 2 weeks. Mice with hypothalamic lesions had decreased goitre development (Moll et al., 1969).

Methylthiouracil given at a concentration of 0.1% in the drinking-water to male Wistar rats for 3 weeks led to disappearance of thyroid peroxidase activity from the follicular cells, measured by histochemistry; however, the activity reappeared after prolonged treatment for 6 months (Christov & Stoichkova, 1977).

Wistar rats treated with 0.1% methylthiouracil in their drinking-water had a fourfold increase in thyroid weights within 3 months and a 10-fold increase within 15 months. The mitotic index had increased by 10–15-fold in hyperplastic and malignant cells at 9 months (Christov, 1985).

4.3. Reproductive and developmental effects

No data were available to the Working Group.

4.4. Effects on enzyme induction or inhibition and gene expression

No data were available to the Working Group.

4.5. Genetic and related effects

4.5.1. Humans

No data were available to the Working Group

4.5.2. Experimental systems (see Table 1 for references)
Table 1. Genetic and related effects of methylthiouracil.

Table 1

Genetic and related effects of methylthiouracil.

Methylthiouracil was not mutagenic to Salmonella typhimurium in an assay with preincubation when tested with or without metabolic activation. It induced somatic recombination in eye cells in all three strains of Drosophila melanogaster tested when administered continuously in feed to larvae.

Methylthiouracil did not induce micronucleus formation in male mice after intraperitoneal injection or oral gavage [details not provided]. When the drug was administered orally in two doses to pregnant mice, it appeared to increase the frequency of micronucleated polychromatic erythrocytes in the fetuses, but no micronucleus formation was seen in maternal bone-marrow cells. However, it is not clear that the same or similar cell populations were observed in the control and treated groups (the percentages of nucleated cells were quite different), and there was no significant increase in the number of micronucleated cells at doses of 5–100 mg/kg bw.

4.6. Mechanistic considerations

Inadequate data were available on the genotoxicity of methylthiouracil.

Methylthiouracil belongs to a class of drugs used in the treatment of hyperthyroidism. The mode of action is inhibition of thyroid peroxidase, which decreases thyroid hormone production and increases follicular-cell proliferation by increasing the secretion of thyroid-stimulating hormone. This is assumed to be the basis of the tumorigenic activity of methylthiouracil in the thyroid in experimental animals; however, the lack of adequate data limits the confidence with which conclusions can be drawn.

The lack of adequate data on genotoxicity for methylthiouracil precludes a conclusion regarding the mechanism of carcinogenesis.

5. Summary of Data Reported and Evaluation

5.1. Exposure data

Methylthiouracil is a thionamide anti-thyroid drug, introduced in the 1940s, which has been used in the treatment of hyperthyroidism. Little is known about its current use.

5.2. Human carcinogenicity studies

No epidemiological data on use of methylthiouracil 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, methylthiouracil has produced tumours in three species of laboratory rodents after oral administration. In two studies in mice, multiple studies in rats and one study in hamsters, methylthiouracil produced thyroid follicular-cell adenomas and/or carcinomas after oral administration. In initiation–promotion studies with the known carcinogens 2-acetylaminofluorene and N-methyl-N-nitrosourea, methylthiouracil increased the incidence of thyroid follicular-cell tumours.

5.4. Other relevant data

Little is known about the disposition of methylthiouracil in humans. In rats, methylthiouracil was found to accumulate in the thyroid. The compound crosses the placental barrier and is transferred rapidly across the placenta throughout gestation.

Human exposure to methylthiouracil is associated with a high frequency of agranulocytosis.

The available data on the mechanism of action of methylthiouracil in experimental animals is limited, but inhibition of thyroid peroxidase and increased secretion of thyroid-stimulating hormone may be the basis of its tumorigenic activity in the thyroid.

No data were available on reproductive or developmental effects of methylthiouracil.

Methylthiouracil was not mutagenic in single studies of reverse mutation in bacteria and bone-marrow micronucleus formation in rodents. It induced chromosomal recombination in somatic cells of insects. It gave an inconclusive response in a test for micronucleus formation in fetal mouse blood cells.

5.5. Evaluation

There is inadequate evidence in humans for the carcinogenicity of methylthiouracil.

There is sufficient evidence in experimental animals for the carcinogenicity of methylthiouracil.

Overall evaluation

Methylthiouracil is possibly carcinogenic to humans (Group 2B).

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PROPYLTHIOURACIL

This substance was considered by previous working groups, in 1974 (IARC, 1974) and 1987 (IARC, 1987). Since that time, new data have become available, and these have been incorporated into the monograph and taken into consideration in the present evaluation.

1. Exposure Data

1.1. Chemical and physical data

1.1.1. Nomenclature
  • Chem. Abstr. Serv. Reg. No.: 51-52-5
  • Deleted CAS Reg. No.: 500-50-5
  • Chem. Abstr. Name: 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone
  • IUPAC Systematic Name: 6-Propyl-2-thiouracil
  • Synonyms: 6-n-Propyl-2-thiouracil; 6-n-propylthiouracil; 6-propyl-2-thio-2,4-(1H,3H)pyrimidinedione; 6-propylthiouracil; PTU; 2-thio-4-oxy-6-propyl-1,3-pyrimidine; 2-thio-6-propyl-1,3-pyrimidin-4-one
1.1.2. Structural and molecular formulae and relative molecular mass
Image 91a
1.1.3. Chemical and physical properties of the pure substance
1.1.4. Technical products and impurities

Propylthiouracil is available as 25- or 50-mg tablets (Gennaro, 1995; American Hospital Formulary Service, 2000; Herbrand, 2000).

Trade names for propylthiouracil include Procasil, Propacil, Propycil, Propyl-Thiocil, Propyl-Thyracil, Propylthiorit, Prothiucil, Prothiurone, Prothycil, Prothyran, Protiural, Thiuragyl, Thyreostat II and Thiotil.

1.1.5. Analysis

Several international pharmacopoeias specify infrared absorption spectrophotometry with comparison to standards, thin-layer chromatography and colorimetry as methods for identifying propylthiouracil; potentiometric titration and titration with sodium hydroxide are used to assay its purity. In pharmaceutical preparations, propylthiouracil is identified by infrared and ultraviolet absorption spectrophotometry and high-performance liquid chromatography (HPLC) with ultraviolet detection; HPLC with ultraviolet detection and titration with sodium hydroxide or mercury nitrate are used to assay for propylthiouracil content (British Pharmacopoeial Commission, 1993; Society of Japanese Pharmacopoeia, 1996; Council of Europe, 1997; AOAC International, 1998; US Pharmacopeial Convention, 1999).

Methods have been reported for the analysis of propylthiouracil in biological fluids (blood, milk, serum, urine), tissues, dried animal feed, feed additives and drugs. The methods include potentiometric titration, capillary zone electrophoresis with ultraviolet detection, micellar electrokinetic chromatography, thin-layer chromatography, high-performance thin-layer chromatography, HPLC with atmospheric pressure chemical ionization mass spectrometry, reversed-phase HPLC with ultraviolet detection and gas chromatography with mass spectrometry (Saldaña Monllor et al., 1980; Moretti et al., 1986, 1988; Centrich Escarpenter & Rubio Hernández, 1990; De Brabander et al., 1992; Moretti et al., 1993; Krivánková et al., 1996; Blanchflower et al., 1997; Ciesielski & Zakrzewski, 1997; Le Bizec et al., 1997; Yu et al., 1997; Buick et al., 1998; Vargas et al., 1998; Esteve-Romero et al., 1999).

1.2. Production

Propylthiouracil can be prepared by the condensation of ethyl β-oxocaproate with thiourea (Anderson et al., 1945).

Information available in 2000 indicated that propylthiouracil was manufactured by three companies in Germany, two companies in Japan and one company in Brazil (CIS Information Services, 2000a).

Information available in 2000 indicated that propylthiouracil was used in the formulation of pharmaceutical drugs by four companies in the USA, three companies in Germany, two companies each in Austria, Canada, Thailand and the United Kingdom and one company each in Australia, Belgium, Brazil, Israel, Japan, Portugal, the Republic of Korea, Singapore, Sweden, Switzerland and Turkey (CIS Information Services, 2000b).

1.3. Use

Propylthiouracil has been used since the 1940s in the treatment of hyperthyroidism. The starting doses are usually 100–150 mg three times a day orally; higher doses, up to 2400 mg/day, have been used in severe thyrotoxicosis. There are no intravenous preparations, but rectal use has been reported (Cooper, 1998). The dose of propylthiouracil is not different for infants, children or the elderly, and it is considered unnecessary to alter the dose for patients with hepatic or renal disease (Cooper, 2000). In the USA, propylthiouracil is used as the primary therapy for hyperthyroidism in pregnancy (Masiukiewicz & Burrow, 1999). The doses used are similar to those for non-pregnant women, with an effort to minimize them when possible to avoid fetal hypothyroidism. Propylthiouracil has also been deemed safe for use by lactating women (Cooper, 1987; Momotani et al., 2000).

Anti-thyroid drugs, including propylthiouracil, may be given for several weeks up to 1–2 years for the treatment of hyperthyroidism. After initiation of therapy, thyroid function improves slowly, returning to normal only by 6–12 weeks of treatment (Okamura et al., 1987). The time that it takes a patient to achieve a euthyroid state depends on a variety of clinical factors, including the severity of the hyperthyroidism at baseline, the size of the thyroid (correlated with intrathyroidal hormonal stores) and the dose of the anti-thyroid drug. Often, as thyroid function improves, the doses of anti-thyroid drug can be reduced. For example, maintenance doses of 50–150 mg of propylthiouracil per day may be adequate to control thyroid function for an extended period. Low doses of anti-thyroid drugs are most successfully used in areas of the world with marginal iodine sufficiency, as high intrathyroidal iodine concentrations would be expected to offset the effects of the drugs (Azizi, 1985).

Propylthiouracil has been investigated as a possible therapy for alcoholic hepatitis (Orrego et al., 1987), the rationale being that the induction of a hypothyroid state might decrease hepatic oxygen requirements, or that propylthiouracil might function as a free-radical scavenger. However, this use has not gained much support (Orrego et al., 1994).

By inducing hypothyroidism, propylthiouracil can increase the body weight of cattle (Thrift et al., 1999), but the use of thyrostatic drugs for this purpose is forbidden in the European Union (European Commission, 1981) and by the Department of Agriculture (2000) in the USA.

1.4. Occurrence

1.4.1. Occupational exposure

According to the 1981–83 National Occupational Exposure Survey (National Institute for Occupational Safety and Health, 2000), about 3300 workers, comprising mainly pharmacists and laboratory workers in health services, were potentially exposed to propylthiouracil in the USA.

1.4.2. Environmental occurrence

No data were available to the Working Group.

1.5. Regulations and guidelines

Propylthiouracil is listed in the pharmacopoeias of China, France, Germany, Japan, the United Kingdom and the USA and also in the European and International Pharmacopoeias (Society of Japanese Pharmacopoeia, 1996; Council of Europe, 1997; Royal Pharmaceutical Society of Great Britain, 2000; Swiss Pharmaceutical Society, 2000), and it is registered for human use in Norway, Sweden, Portugal and the United Kingdom (Instituto Nacional de Farmacia e do Medicamento, 2000; Medical Products Agency, 2000; Medicines Control Agency, 2000; Medicines Evaluation Board Agency, 2000; Norwegian Medicinal Depot, 2000).

2. Studies of Cancer in Humans

No information was available specifically on propylthiouracil.

2.1. Cohort studies

Dobyns et al. (1974) followed up 34 684 patients treated in England and the USA for hyperthyroidism between 1946 and 1964, 1238 of whom had been treated for at least 1 year with unspecified anti-thyroid drugs. No malignant thyroid neoplasm was found within 1 year of treatment. By 1968, more cases of thyroid neoplasm were found at follow-up among patients initially treated with anti-thyroid drugs (4 malignant tumours and 18 adenomas in 1238 patients) than among those initially treated with 131I (19 malignant tumours and 41 adenomas in 21 714 patients) or (partial) thyroidectomy (4 malignant tumours and 14 adenomas in 11 732 patients). The authors suggested that more neoplasms were found in the drug-treated patients because subsequent thyroidectomy was more frequent in this group (30% of drug-treated patients, as compared with 0.5% of those initially treated with 131I and 1.2% of those treated with primary thyroidectomy), which provided more opportunity for identification of neoplasms. [The Working Group noted that rates could not be calculated because person–years were not provided, and the ages of the groups were not given.]

Ron et al. (1998) updated the report of Dobyns et al. (1974) and followed-up 35 593 patients treated for hyperthyroidism between 1946 and 1964 in 25 clinics in the USA and one in the United Kingdom. By December 1990, about 19% had been lost to follow-up, and 50.5% of the study cohort had died. A total of 1374 patients (1094 women) had been treated with anti-thyroid drugs only, 10 439 (7999 women) with 131I and drugs, 10 381 (8465 women) with thyroidectomy and drugs, 2661 (2235 women) with a combination of the three types of treatment and the remainder by other means. The drugs used during the study period were chiefly thiourea derivatives and iodine compounds. One year or more after the start of the study, the standardized mortality ratio (SMR) in comparison with the general population for the patients treated with anti-thyroid drugs only was 1.3 (95% confidence interval [CI], 1.1–1.6) for deaths from all cancers, which was chiefly due to significantly more deaths from oral cancer (4.2; 95% CI, 1.3–9.7; five cases) and brain tumours (3.7; 95% CI, 1.2–8.6; five cases). The excess risk for death from brain cancer persisted after exclusion of cases prevalent at the time of entry into the study. No deaths from thyroid carcinoma were recorded. The SMR for all cancers was approximately 1.0 in patients treated with 131I or surgery (with or without anti-thyroid drugs), but the SMR for thyroid cancer was fourfold higher (3.9; 95% CI, 2.5–5.9; 24 cases observed) among patients who had been treated with 131I with or without drugs. The authors noted that the group treated with drugs only was small; the type, quantity and dates of drug use were generally not available; and many patients had cancer before entry into the study, suggesting that some, but not all, of the excess could be attributed to the selection of patients with health problems for drug therapy. [The Working Group noted that the expected number of deaths from thyroid carcinomas was not reported, although it would almost certainly have been less than 1.0. Results were given separately for patients treated only with drugs and not for those given drugs with other treatment.]

2.2. Case–control studies

Ron et al. (1987) conducted a study of 159 cases of thyroid cancer and 285 population controls in Connecticut, USA, between 1978 and 1980. The use of anti-thyroid medications was not associated with an increased risk [relative risks not shown].

In a study carried out in northern Sweden between 1980 and 1989, 180 cases of thyroid cancer and 360 population controls were evaluated (Hallquist et al., 1994). Use of anti-thyroid drugs (two cases and two controls) was associated with a relative risk of 2.0 (95% CI, 0.2–21).

3. Studies of Cancer in Experimental Animals

Propylthiouracil was evaluated in a previous monograph (IARC, 1974). Because there have been only four new studies on the carcinogenicity of propylthiouracil in animals and none that are conventional bioassays in rodents, the most relevant studies from the previous monograph were analysed in greater depth. Studies on the carcinogenicity of anti-thyroid chemicals, including propylthiouracil, in experimental animals have been reviewed (Doniach, 1970; Christov & Raichev, 1972; Paynter et al., 1988).

3.1. Oral administration

Mouse: Groups of male strain A mice [initial numbers not specified, but presumed to be four], 4–6 weeks of age, received a commercial diet containing 0.8% propylthiouracil [purity not specified] for up to 534 days. Thyroid follicular-cell carcinomas (two of which metastasized to the lungs) were present in all four propylthiouraciltreated mice and chromophobe adenomas of the anterior lobe of the pituitary gland in three of these mice. The anterior pituitary glands of a similar group of surgically thyroidectomized mice were normal (Moore et al., 1953). [The Working Group noted the small numbers of animals in the groups.]

Groups of 60 C57BL mice [sex not specified], 4–5 weeks of age, were fed a diet containing propylthiouracil [purity not specified] at a concentration of 0 (control), 10 or 12 g/kg of diet for 17 months. The survival rate in all groups was approximately 50%. Pituitary adenomas occurred in 15/24 and 21/29 mice at the two concentrations, respectively, and in 0/28 control mice. Thyroid follicular-cell hyperplasia was grossly apparent in the treated mice. Administration of 2,4-dinitrophenol (an inhibitor of thyrotropin release) at 0.5 g/kg of diet in conjunction with the two doses of propylthiouracil reduced the incidence of pituitary tumours by at least 75% in each case, and no thyroid hyperplasia was apparent in these mice (King et al., 1963).

Rat: Two groups of young adult white rats [number per group, sex, age and strain not specified] were given drinking-water containing propylthiouracil [purity not specified] at a concentration of 0.1%. One of the groups received propylthiouracil and potassium iodide alternately, the latter at a concentration of 0.01% in the drinking-water [exact protocol not stated]. The study was terminated within 1 year, when the total survival rate in the two groups was 44 of the original 100 rats. Thyroid follicularcell tumours occurred in 4/15 survivors given propylthiouracil alone and in 20/29 survivors treated with propylthiouracil and potassium iodide alternately. All but one of the tumours were thyroid adenomas, the exception being a thyroid carcinoma in a rat given propylthiouracil plus potassium iodide (Zimmerman et al., 1954).

Groups of male and female Wistar rats [group size presumed to be 55 of each sex], 6–8 weeks of age, received propylthiouracil [purity not specified] at a concentration of 0.2% in their drinking-water alone or after a single intraperitoneal injection of 30 µCi of 131I. Because of a high mortality rate, the concentration of propylthiouracil given to both groups was reduced to 0.1% at 3 months, 0.05% at 6 months and 0.025 % at 1 year. In a second part of the experiment, 25 rats [number of each sex not specified] received a low concentration of propylthiouracil in their drinking-water, adjusted to provide a dose of 7 mg/kg bw per day initially (approximately equivalent to the human clinical dose) and then reduced to 1 mg/kg bw per day over 3 months. The control groups comprised 20 untreated male and 20 untreated female rats on normal diet. The treatments were continued until termination at 18 months, but control rats were continued until approximately 20 months of age. In the groups receiving 0.2% propylthiouracil alone, thyroid follicular-cell adenomas occurred in 11/18 males and 20/30 females and thyroid carcinomas in 3/18 males and 4/30 females. In the groups receiving 0.2% propylthiouracil plus 131I, thyroid adenomas occurred in 9/15 males and 16/24 females and thyroid carcinomas in 4/15 males and 6/24 females. In the groups that initially received propylthiouracil at 7 mg/kg bw per day, thyroid adenomas occurred in 2/5 males and 7/13 females and thyroid carcinomas in 1/5 males and 2/13 females. In the untreated control groups, thyroid adenomas occurred in 2/20 males and 1/20 females, but there were no carcinomas in either sex (Willis, 1961).

Groups of 99–112 male Long Evans rats, 6 weeks of age, were fed a diet containing propylthiouracil [purity not specified] at a concentration of 0.1% (100 rats), the same diet after a single intraperitoneal injection of 25 µCi of 131I in 0.5 mL of distilled water (112 rats), propylthiouracil in combination with 131I plus dessicated thyroid powder at a concentration of 250 mg/kg of diet (99 rats) or propylthiouracil plus dessicated thyroid powder (99 rats). Additional groups consisted of untreated controls (101 rats), rats receiving 131I only (106 rats), rats receiving dessicated thyroid powder only (103 rats) and rats receiving 131I plus dessicated thyroid powder (106 rats). Each group was maintained on its specific diet for 1 year, at which time the study was terminated. In the group receiving 0.1% propylthiouracil alone, thyroid follicular-cell adenomas occurred in 16/33 survivors. With propylthiouracil in combination with 131I, 23/35 rats had thyroid adenomas, while in the group given propylthiouracil plus 131I plus dessicated thyroid powder, 64/65 rats developed thyroid tumours, of which 51 were adenomas and 13 carcinomas. In the group given propylthiouracil plus dessicated thyroid powder, 43/60 rats developed thyroid tumours, of which 39 were adenomas and 4 carcinomas. None of 68 untreated control rats had adenomas or papillary or follicular carcinomas (Lindsay et al., 1966).

In a study published since the previous evaluation, groups of four to six male albino rats, 4 months of age, were given propylthiouracil [purity not specified] in the drinking-water at a concentration of 60 µg/mL for 3, 5, 7 or 9 months 1 week after a single intraperitoneal injection of 25 µCi of 131I in 0.5 mL of saline with or without l-thyroxine in the drinking-water at a concentration of 0.5 µg/mL. Control groups of four rats received no irradiation, propylthiouracil or thyroxine. In the groups given 131I plus propylthiouracil, thyroid tumours occurred in 1/4, 5/5 and 6/6 rats at 5, 7 and 9 months, respectively. In the groups given 131I plus propylthiouracil plus thyroxine, thyroid follicularcell tumours occurred in 1/4 and 5/5 rats at 7 and 9 months, respectively. There were no thyroid tumours in the control rats (Al-Hindawi et al., 1977). [The Working Group noted the small numbers of animals in each group.]

Hamster: Groups of 214 male and 197 female Syrian golden hamsters, 3 months of age, were given drinking-water containing propylthiouracil [purity not specified] at a concentration of 0.2% for up to 133 weeks for males and 113 weeks for females. A control group of 205 males and 146 females were fed a diet with no propylthiouracil. The survival rate was reported not to be markedly influenced by treatment, the mean lifespans being 636, 500, 568 and 500 days for control males and females and treated males and females, respectively. Twelve animals per group were selected for eight interim killings for biochemical analyses. Thyroid follicular-cell cancer was diagnosed in 13/58 males and 9/44 females exposed to propylthiouracil, and an additional four males and six females had thyroid cancer that had metastasized to the lungs or lymph nodes. The thyroid tumour incidence in the control hamsters was not given, but a historical control incidence of 1.5% was cited (Fortner et al., 1960). The combined tumour incidence for males and females treated with propylthiouracil was statistically significantly greater than 1.5% (p < 0.01) (Sichuk et al., 1968). [The Working Group noted the lack of data on concurrent controls.]

Guinea-pig: Groups of 20 male guinea-pigs weighing 600–900 g [age and strain not specified] were given propylthiouracil [purity not specified] in their drinking-water at a concentration of 0.03% for up to 24 months, with or without a series of seven subcutaneous injections of 1 mL of thyroid-lipid extract emulsified in physiological saline given over the course of the study. Two groups of five control animals received the same regimen but without propylthiouracil. The survival rate at the end of the study at 24 months was 30–35% in the propylthiouracil-treated groups and 60% in the control groups. The incidence of animals with thyroid follicular-cell adenomas was 3/20 with propylthiouracil only and 12/20 with propylthiouracil plus thyroid-lipid extract, in contrast to none in either control group (Hellwig & Welch, 1963).

3.2. Administration with known carcinogens

Four studies in which rats were treated with propylthiouracil in combination with known carcinogens have been published since the previous evaluation.

Groups of female Fischer 344 rats, 50 days of age, received a single intravenous injection of N-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg bw. Five days later, groups of 30 rats were given propylthiouracil [purity not specified] in their drinking-water at concentrations of 0.3, 1.0 or 3.0%. A control group of 12 rats received no treatment, and 43 rats received the initiating dose of MNU alone. The incidence of thyroid follicular-cell tumours was increased from 0/12 controls and 0/43 receiving MNU only to 12/30, 30/30 and 30/30 with the increasing doses of propylthiouracil, respectively (Milmore et al., 1982).

Two groups of 21 male inbred Wistar rats, 6 weeks of age, were fed basal diet containing propylthiouracil [purity not specified] at a concentration of 0.15% either alone or in combination with a single intraperitoneal injection of N-nitrosobis(2-hydroxypropyl)amine (NBHPA) at the start of the study at a dose of 2.8 g/kg bw. Two additional groups received the initiating dose of NBHPA alone or basal diet alone (control group). The animals were maintained for 20 weeks, at which time the survival rate was 100%. Thyroid follicular-cell tumours occurred in 21/21 rats given NBHPA plus propylthiouracil, 4/21 given NBHPA only (p < 0.05) and 0/21 given propylthiouracil only or no treatment. Of the rats given NBHPA plus propylthiouracil, seven of those bearing thyroid tumours had thyroid carcinomas (Kitahori et al., 1984).

Two groups of 20 male inbred Wistar rats, 8 weeks of age, were given basal diet containing propylthiouracil [purity not specified] at a concentration of 0.1% for 19 weeks either alone or in combination with a single intraperitoneal injection of NBHPA (purity, 99.8%) at 7 weeks of age at a dose of 2.8 g/kg bw. Two additional groups received the initiating dose of NBHPA alone or basal diet alone. The survival rate at the end of the experiment was 100% for all groups. Thyroid follicular-cell adenomas occurred in 19/20 rats receiving NBHPA plus propylthiouracil, 1/20 treated with NBHPA alone (p < 0.05) and 0/20 receiving propylthiouracil or basal diet alone (Hiasa et al., 1987).

Female Sprague-Dawley rats, 50–60 days of age, were given 7,12-dimethylbenz[a]anthracene (DMBA) in sesame oil by oral gavage at a dose of 6.5, 10, 13.5 or 15 mg per animal. Propylthiouracil was given in the drinking-water at concentrations between 0.5 and 4.0 mg/100 mL for various times before and after the DMBA treatment, ranging from 17 days before DMBA up to the end of the study at 4 months. Severe hypothyroidism produced by administration of propylthiouracil at the higher dose from 7 days before DMBA up to study termination reduced the mammary tumour incidence from 68/108 in rats given DMBA only to 3/45 in those given DMBA plus propylthiouracil (Goodman et al., 1980).

4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms

4.1. Absorption, distribution, metabolism and excretion

4.1.1. Humans

In seven healthy persons (six men and one woman) given an intravenous injection of 400 mg of propylthiouracil, the average half-time of the drug was 77 min. In a two-compartmental equation, the total clearance was calculated to be 112 mL/min per m2. When the same dose was given orally, the average maximum serum concentration of propylthiouracil was 9.1 µg/mL and was reached at 57 min (average for the seven subjects). The total volume of distribution was calculated to be 30% of the body weight, and the bioavailability of propylthiouracil was determined to be 77% (range, 53–88%) (Kampmann & Skovsted, 1974). After intravenous infusion of propylthiouracil into three men and one woman, the half-time and total body clearance were similar to those after injection, but the total volume of distribution (40%) was slightly larger (Kampmann, 1977). In another study, oral administration of a smaller dose of propylthiouracil (200 mg) to six subjects showed a similar half-time, viz 1.1 h (Sitar & Hunninghake, 1975). Ringhand et al. (1980) calculated a half-time of 1.24–1.4 h after oral administration of propylthiouracil.

In a study in which propylthiouracil was given as a single oral dose of 300 mg to eight healthy volunteers (five women and three men) in either the fasting state or after a standardized breakfast, absorption of the drug was found to be influenced by inter-individual variation but to only a minor extent by food intake (Melander et al., 1977). The severity of hyperthroidism and prior exposure to propylthiouracil were reported to affect the rate of elimination after oral administration of 3 mg/kg bw to 10 women and seven men. In patients with mild to moderate hyperthyroidism, elimination of the first dose of propylthiouracil was faster than the elimination in the same individual after 1 month of therapy, whereas in patients with severe hyperthyroidism, elimination of the first dose was inhibited. No changes in absorption rate were reported (Sitar et al., 1979).

When patients undergoing thyroidectomy were given [35S]propylthiouracil orally at 100 µCi 3–48 h before surgery, the compound accumulated in the thyroid but not in thyroid neoplasms (Marchant et al., 1972).

In one person given 51 mg of [35S]propylthiouracil orally, propylthiouracil glucuronide was the major excretion product (86%) in urine between 0 and 6 h, whereas at 8.8–23 h, a sulfate conjugate was the major urinary metabolite (Taurog & Dorris, 1988).

Placental transfer of [35S]propylthiouracil was examined in four women who were 8–16 weeks pregnant and undergoing therapeutic abortions. The women were given 15 mg (100 µCi) of propylthiouracil orally. The average fetal:maternal serum ratio of radiolabel, obtained for two women, was 0.31. Accumulation of radiolabel in the fetal thyroid was noted (Marchant et al., 1977). Six pregnant hyperthyroid women were given an oral dose of 100 mg of propylthiouracil. The serum profiles of the drug during the third trimester of pregnancy were qualitatively similar to those in nonpregnant women, but the concentrations were consistently lower in the late third trimester than those seen post partum. The cord serum concentrations were higher than those in maternal serum collected simultaneously (Gardner et al., 1986).

In isolated, perfused, term human placentae, propylthiouracil at doses of 4 and 40 µg/mL in either a protein-free perfusate or a perfusate containing 40 g/L bovine serum albumin readily crossed the placenta and reached equilibrium within 2 h. The binding of propylthiouracil to bovine serum albumin, measured by ultrafiltration, was 94.5% and that to human serum albumin was 60.6%. The transfer of propylthiouracil was similar to that of methimazole (Mortimer et al., 1997).

4.1.2. Experimental systems

In male Sprague-Dawley rats given [14C]propylthiouracil intravenously, intraperitoneally or orally at a dose of 20 mg/kg bw, equilibrium dialysis indicated that 57% of the drug in plasma was bound to protein. No particular affinity for any tissue was noted. Between 75% and 90% of the administered radiolabel was excreted in the urine and approximately 15% in the bile. The half-time was 4–6 h by all routes of administration. Between 9 and 15% of the initial dose was excreted unchanged within 24 h. The major urinary metabolite was propylthiouracil glucuronide (40–48% in 24-h urine samples), but a different glucuronide conjugate of propylthiouracil appeared to be excreted in bile (Sitar & Thornhill, 1972). Another group of rats given [35S]propylthiouracil intraperitoneally at 1.2 µmol [204 µg] per animal showed accumulation of the propylthiouracil in the thyroid (Marchant et al., 1972). Other authors have reported a similar bile metabolite (Papapetrou et al., 1972; Lindsay et al., 1974; Taurog & Dorris, 1988). Taurog and Dorris (1988) reported that propylthiouracil was the main excretion product, accounting for 34% of the administered radiolabel, and propylthiouracil glucuronide accounted for 32%. In a study with both [14C]- and [35S]propylthiouracil in the same strain of rats, unaltered propylthiouracil comprised 42% of the total urinary output, an unidentified metabolite 22% and propylthiouracil glucuronide 16%. Additional minor metabolites have been reported in both urine and bile (Lindsay et al., 1974).

In CD rats given drinking-water containing propylthiouracil at concentrations of 0.0001–0.01% for 1 week or 1 month, the compound was cleared from the serum by bi-exponential disappearance, and an initial increase in the thyroid content of propylthiouracil was seen. Thereafter, the concentration in the thyroid declined linearly (Cooper et al., 1983).

In the same strain of rats and with a radioimmunoassay specific for propylthiouracil, the serum concentration was reported to be a linear function of the dose (0.0001–0.05% in drinking-water), while the thyroid concentration was a linear function of the logarithm of the dose. The serum propylthiouracil concentrations were higher after 1 month of treatment than after 1 week. These results were consistent with a multi-compartmental model for the distribution of propylthiouracil (Halpern et al., 1983).

Placental transfer of 14C-labelled propylthiouracil was demonstrated in pregnant rats on day 14 of gestation after injection of 1 µCi of the compound. The label was cleared from the fetus within 24 h (Hayashi et al., 1970).

When Sprague-Dawley rats were given intravenous injections of [14C]propylthiouracil (4.1 µmol [698 µg]) on days 19 and 20 of gestation, the fetal:maternal serum concentration ratio was < 1 during 2 h after injection (Marchant et al., 1977).

Nakashima et al. (1978) reported that the intrathyroidal metabolism of propylthiouracil in male Sprague-Dawley rats was strongly influenced by the dose (0.18–59 µmol [31 µg–10 mg] intraperitoneally). Propylthiouracil inhibited its own intrathyroidal metabolism.

Metabolism of propylthiouracil in activated neutrophils resulted in three oxidized metabolites: propylthiouracil-disulfide, propyluracil-2-sulfinate and propyluracil-2sulfonate. The metabolism was inhibited by sodium azide and catalase and by propylthiouracil itself (Waldhauser & Uetrecht, 1991).

The metabolism of the drug was either reversible or irreversible, depending on iodination conditions, in an in-vitro system containing thyroid peroxidase. Propylthiouracil disulfide was the earliest detectable metabolite (Taurog et al., 1989).

4.1.3. Comparison of animals and humans

In both humans and laboratory animals, propylthiouracil is quickly absorbed and uniformly distributed, apart from concentration in the thyroid of adults and fetuses. It is rapidly excreted, the main metabolite being a glucuronide in both humans and rats.

4.2. Toxic effects

4.2.1. Humans
(a) Effects on thyroid function at therapeutic doses

Propylthiouracil is commonly used to treat hyperthyroidism. It inhibits intrathyroidal synthesis of thyroid hormones by interfering with thyroid peroxidase-mediated iodine utilization. As a result, the concentrations of thyroxine (T4) and triiodothyronine (T3) in serum are decreased. In addition, and unlike methimazole, propylthiouracil inhibits type-1 deiodinase which converts T4 to T3 in the liver and other tissues (Cooper, 2000). Therefore, serum T3 concentrations fall rapidly after administration of propylthiouracil, sooner than would be expected on the basis of inhibition of thyroidal hormone synthesis.

In some studies, hyperthyroid patients became hypothyroid if the dose of propylthiouracil was not monitored carefully. In one study, 56% of patients became hypothyroid within 12 weeks while taking 400 mg/day (Kallner et al., 1996). With respect to its effects on T4 deiodination, both normal and hyperthyroid patients showed marked decreases in serum T3 concentrations within a few hours of ingesting 50–300 mg of propylthiouracil. The concentration of T3 decreased by up to 50% in hyperthyroid patients, and that of reverse T3 (rT3), an inactive metabolite of T4 that is cleared by type-1 deiodinase (see Figure 1, General Remarks), increased by up to 50% (Cooper et al., 1982). Ten patients with primary hypothyroidism (eight women and two men), who had been receiving 0.1 or 0.2 mg of T4 daily for ≥ 2 months, were given 1000 mg of propylthiouracil daily in combination with 0.1 mg of T4 for 7 days. The average serum T3 concentration decreased from approximately 80 to 60 ng/100 mL, the average concentration of thyroid-stimulating hormone (TSH) increased gradually from approximately 30 to 40 µU/mL (not statistically significant for the whole group), and no changes occurred in T4 concentrations (Saberi et al., 1975). Similar changes were seen when six healthy volunteers (three men and three women) who had been treated with T4 at 200–250 µg/day for 9 days were given 150 mg of propylthiouracil orally four times a day for 5 days. Thus, the T3 serum concentration was reduced and that of rT3 was enhanced. The concentrations rapidly returned to normal after cessation of treatment with propylthiouracil (Westgren et al., 1977). Similar effects were noted when a dose of 200 mg of propylthiouracil was given orally four times a day for 5 days to 19 hypothyroid patients (six men and 13 women) who had been taking 50–200 µg of T4 per day for ≥ 2 months before the study; however, no changes in TSH concentration were seen (Siersbaek-Nielsen et al., 1978).

(b) Other studies in humans

Most of the toxic effects of propylthiouracil are considered to be allergenic, including fever, skin rashes and arthralgia, which occur in 1–10% of patients. Agranulocytosis is the most significant major side-effect, occurring in 0.1–0.5% of patients. (Van der Klauw et al., 1998; Cooper, 1999). Other rare but serious reactions include toxic hepatitis (Williams et al., 1997), vasculitis (often antineutrophil cytoplasmic antibody-positive) (Gunton et al., 1999) and a drug-induced lupus syndrome.

4.2.2. Experimental systems

In female NMRI mice fed a low-iodine diet, administration of drinking-water containing 0.1% propylthiouracil impaired thyroidal uptake of 125I (Ahrén & Rerup, 1987).

The inhibition of thyroid iodide peroxidase (TPO) by propylthiouracil was studied in vivo and in vitro by measuring oxidized iodide. Propylthiouracil was given at a dose of 10 mg by intraperitoneal injection to Wistar rats weighing about 150 g. The activity of TPO in the thyroid gland isolated after 3 h was significantly decreased before dialysis and restored after dialysis. In vitro, the activity of TPO was decreased by incubation with propylthiouracil and restored by dialysis and by dilution. Propylthiouracil interacted directly with the product of TPO (the oxidized iodide) without significantly affecting the activity of TPO itself. At a concentration of 2 × 10−6 mol/L, 50% inhibition occurred (Nagasaka & Hidaka, 1976). In male CD rats given propylthiouracil by intraperitoneal injection at 10–50 mg/kg bw in the absence of oxidizable substrates, irreversible inhibition of TPO was observed. When iodide or thiocyanate was present, inhibition was prevented, suggesting that the initial action of propylthiouracil is to block iodination by trapping oxidized iodide (Davidson et al., 1978). In an iodination system, inactivation of TPO by propylthiouracil involved a reaction between propylthiouracil and the oxidized haem group produced by interaction between TPO and H2O2 (Engler et al., 1982a). A specific inhibitory effect of propylthiouracil on coupling was demonstrated in an incubation system in which TPO catalysed conversion of diiodotyrosine to T4 (Engler et al., 1982b).

When male Sprague-Dawley rats maintained on T4 at 20 or 50 µg/kg bw per day were given propylthiouracil, the conversion of T4 to T3 was inhibited (Oppenheimer et al., 1972). Frumess and Larsen (1975) further studied the role of the conversion of T4 to T3 in thyroidectomized, hypothyroid male Sprague-Dawley rats that were given a subcutaneous injection of T4 at 8 or 16 µg/kg bw per day, with or without an intraperitoneal injection of propylthiouracil at 10 mg/kg bw per day. The rats were killed after 5, 10, 12 or 15 days. At 5 days, propylthiouracil treatment had increased the serum T4 concentration (from 4.9 to 5.7 µg/100 mL) and decreased that of T3 (from 37 to 19 ng/100 mL), resulting in a marked increase in the serum T4:T3 ratio (from 134 to 329). The serum TSH concentration was increased from 165 to 339 µU/mL in propylthiouracil-treated groups, and their weight gain was slower. When daily doses of 30 mg/kg bw were administered orally for 5 weeks to male Sprague-Dawley rats, both the T3 and T4 concentrations in serum were decreased, and a decrease in iodine incorporation was also noted. Increases in TSH concentration, thyroid weight and hyperplasia of the follicular cells were also reported (Takayama et al., 1986). When propylthiouracil was administered to rats in the diet at 30 mg/kg from 3 up to 90 days, it reduced the T3 concentration by 60% and that of T4 by 90%, and increased the thyroid weight (fivefold) and the TSH concentration by more than eightfold. Thyroid-cell proliferation increased by up to 8.5-fold during the first week but had returned to control levels by 45 days (Hood et al., 1999a). Hood et al. (1999b) also correlated TSH concentrations with thyroid weight and with the rate of thyroid follicular-cell proliferation in male Sprague-Dawley rats treated with propylthiouracil (1–300 mg/kg of diet) for 21 days. They suggested that small increases in TSH concentration are sufficient to stimulate thyroid follicular-cell proliferation.

Male Wistar rats were given drinking-water containing 0.01% propylthiouracil for 6 months. The drug first acted on the peripheral metabolism of T4 and subsequently on that of TSH. This induced a rapid increase in plasma TSH concentration during the first week, similar to increases seen in other strains of rats. The TSH plasma concentration had returned to normal by day 17, but then increased continuously until the end of treatment. The pituitary TSH concentration decreased after 24 h of treatment and remained low for 3 weeks, then recovered to normal after 1 month. The thyroid weight increased regularly throughout treatment, and the intrathyroid iodine concentration had decreased by 30-fold after 1 month. Secretion of TSH from the pituitary was found to decrease during the first week of treatment, to recover between 17 days and 1 month, and then to increase again by fourfold with continued treatment. The halftime of TSH was shown to be prolonged by propylthiouracil treatment (Griessen & Lemarchand-Béraud, 1973).

In other studies in male Wistar rats on the secretion of thyroid hormones, infusion of propylthiouracil for 4 h at a rate of 2 mg/h increased the excretion of rT3 in the bile of rats that had also received an infusion of T4, starting 2 h before the propylthiouracil treatment. Infusion of propylthiouracil at 0.05–0.4 mg over 2 h after a pulse of 1 µg of rT3 by intravenous injection increased excretion of rT3 in bile in a dose-dependent manner (Langer & Gschwendtová, 1992). Propylthiouracil at 0.05% in the diet also stimulated excretion of T4 in the bile and faeces of Wistar rats. The compound also stimulated uptake of T4 in liver tissue in vitro (Yamada et al., 1976).

In male Wistar rats given propylthiouracil at a concentration of 0.1% in drinking-water for 20 days (calculated intake, 16 mg/day) and an intraperitoneal injection of 100 µCi of 125I 24 h before sacrifice, the amount of soluble thyroglobulin was decreased by > 50% and the proportion of particulate thyroglobulin was slightly increased. The thyroglobulin from treated animals was poorly iodinated. Incubation of thyroid tissue with propylthiouracil in vitro inhibited thyroglobulin biosynthesis (Monaco et al., 1980).

In liver homogenates from male Wistar rats, the conversion of T4 to T3 was lower in those from rats given 0.05% propylthiouracil in a low-iodine diet. A graded dose of T4 failed to restore conversion activity in these rats (Aizawa & Yamada, 1981). In monolayers of freshly isolated rat hepatocytes, outer-ring deiodination of an intermediate in thyroid hormone metabolism (3,3′-diiodothyronine sulfate) was completely inhibited by 10−4 mol/L propylthiouracil, essentially with no effect on overall 3,3′-diiodothyronine clearance (Otten et al., 1984).

Using a sensitive, specific radioimmunoassay for propylthiouracil, Cooper et al. (1983) examined the effects of propylthiouracil at 0.0001–0.01% in drinking-water for 1 week or 1 month in CD rats. A strong inverse relationship was found between the dose of propylthiouracil and both thyroid hormone biosynthesis and peripheral T4 deiodination. The time for recovery from long-term (1 month) treatment was greater than that from short-term (1 week) treatment (2.8 vs 1.1 days), although the two treatments had quantitatively similar effects on thyroid function.

Whereas 30 mg/kg bw propylthiouracil given to rats daily for 5 weeks increased thyroid weight sevenfold and decreased both T3 and T4 concentrations by 70%, the same treatment produced no changes in the thyroid in squirrel monkeys (Saimiri sciureus). The concentration of propylthiouracil required to inhibit thyroid peroxidase in vitro in microsomes isolated from thyroids was markedly higher for the monkeys (4.1 × 10−6 mol/L) than for rats (8.1 × 10−8 mol/L) (Takayama et al., 1986). These findings suggest that rats are more sensitive to the anti-thyroid effects of propylthiouracil than primates and that inhibition of thyroid peroxidase plays an important role in the anti-thyroid effect of propylthiouracil.

Male Sprague-Dawley rats given 0.05% propylthiouracil in the drinking-water for 17 days showed a decreased (40%) proportion of suppressor T cells in the spleen (Pacini et al., 1983).

Intraperitoneal administration of propylthiouracil at 0.5–1.5 mmol/kg bw (85–255 mg/kg bw) to male Sprague-Dawley rats resulted in dose-related decreases in body and spleen weight and an increase in liver weight. Leukocyte counts were markedly reduced. Histologically, congestion of red pulp in the spleen and vacuolization of the liver were noted (Kariya et al., 1983).

Female Fischer 344 rats were given 0.1% propylthiouracil in the drinking-water for 3, 7, 14 or 28 days and observed 3, 7 and 14 days after cessation of treatment. During propylthiouracil ingestion, growth hormone-producing cells in the pituitary gland lost their secretory granules, became enlarged and displayed progressive dilatation of rough endoplasmic reticulum, becoming thyroidectomy cells. This effect was reversible: 14 days after treatment ceased, the normal pituitary structure was seen (Horvath et al., 1990).

Young (3 months) and aged (26 months) male Lewis rats were given drinking-water containing 0.05% propylthiouracil for 4 weeks. In the younger animals, propylthiouracil increased the percentage of sphingomyelin in synaptosomes from the cerebral cortex. In contrast, a decrease in glycerophosphocholine concentration and an increase in that of cholesterol were noted in aged rats (Salvati et al., 1994).

4.3. Reproductive and developmental effects

4.3.1. Humans

A review of the clinical literature resulted in limited information on the risk of propylthiouracil-induced malformations in newborns, but the authors noted that an estimated 1–5% of women treated with propylthiouracil during pregnancy have infants who develop significant transient hypothyroidism (Friedman & Polifka, 1994).

Neonatal goitre was observed in one of a dizygotic set of twins whose mother had received propylthiouracil during pregnancy at an initial dose of 400 mg/day, which was subsequently reduced to 100 mg/day. The reason for the apparently selective effect of propylthiouracil on one of the twins was not clear. The goitre receded within 2 weeks, without therapy (Refetoff et al., 1974).

In 20 women who had received propylthiouracil during the third trimester of pregnancy at doses of 50–400 mg/day, four cases of neonatal goitre, one of thyrotoxicosis, three pregnancy losses and two malformations occurred (Mujtaba & Burrow, 1975). [The Working Group noted that many of these outcomes may have been related to the underlying condition.] In a follow-up study, the intellectual capacity of 18 children whose mothers received propylthiouracil during pregnancy was compared with that of 17 siblings who had not been exposed. The two groups did not differ in a standard intelligence test, the Peabody test, the Goodenough test or on a number of physical characteristics (Burrow et al., 1968). Similarly, no differences were noted in the distribution of IQs in a group of 28 children who had been exposed to propylthiouracil in utero (23 exposed at least in the third trimester) due to treatment of maternal Graves disease and in 32 unexposed siblings (Burrow et al., 1978).

In six pregnant hyperthyroid women who received a daily oral dose of 50, 100 or 150 mg of propylthiouracil, a significant inverse correlation (r = −0.92; p = 0.026) was found between the area under the curve for concentration–time for maternal serum propylthiouracil in the third trimester and the index of free T4 in cord serum (Gardner et al., 1986).

In a study of 34 women with Graves hyperthyroidism who received propylthiouracil during pregnancy, 6% (2/34) of cord blood samples contained free T4 at concentrations below the normal range, while 21% (7/34) had concentrations of TSH above the normal range. All the infants with low free T4 or high TSH concentrations were clinically euthyroid and none had goitre at birth (Momotani et al., 1997).

Transient neonatal hypothyroidism was seen in the offspring of 11 women who had received propylthiouracil at a dose of 100–200 mg/day at term [route unspecified] for Graves disease during pregnancy. The controls were 40 infants born around the same time. The free and total serum T4 concentrations, but not that of T3, were significantly lower in the exposed infants 1 and 3 days after birth (Cheron et al., 1981).

4.3.2. Experimental systems

Testicular growth and serum testosterone concentrations were studied in groups of 8–24 male offspring at 90, 135, 160 and 180 days of age after administration of propylthiouracil in the drinking-water at 0.1% w/v to their lactating Sprague-Dawley dams from the day of parturition until day 25. The growth of treated offspring was reduced up to 25 days of age and then generally paralleled that of control animals, but their body weight remained lower than that of the controls. At all ages studied, the testis weights were increased in the propylthiouracil-exposed groups, despite reductions in body weights. For example, at 90 days of age, the testis weight was increased by 41%, while the body weight was reduced by 22%. Histologically, there was evidence of enhancement of normal spermatogenesis. Epidydymal, seminal vesicle and ventral prostate weights were also increased, but this effect was not apparent until 135 days of age. The weights of non-reproductive organs (e.g. brain, liver, pituitary and salivary glands) were reduced in the exposed groups. There was no effect on serum T4, T3 or testosterone concentration at any adult age, and there were no obvious histological changes in any tissue. Administration of T4 at 15 µg/kg bw per day and T3 at 10 µg/kg bw per day to pups during exposure to propylthiouracil abolished the effects on testicular growth (Cooke & Meisami, 1991). A subsequent study showed an increase in daily sperm production of 83–136%, depending on age (Cooke et al., 1991). The increases in testis weight and daily sperm production could not be induced by prenatal exposure to propylthiouracil (gestation day 16 to birth) or by exposure beginning after postnatal day 8 (Cooke et al., 1992). While the serum testosterone concentration was not permanently affected by this treatment, the circulating gonadotropin concentration remained 30–50% lower than that in controls throughout adulthood, an effect related to impairment of gonadal feedback and gonadotrope synthetic ability (Kirby et al., 1997). These results suggest a direct impairment of gonadotropin-releasing hormone regulation of gonadotrope development.

Of six interstitial cell types, only Leydig cells showed an increased mitotic labelling index in male pups of rat dams given propylthiouracil at 0.1% in the drinking-water from the day of parturition to the time of weaning 24 days post partum (Hardy et al., 1996). The total number of Leydig cells in the testes of 180-day-old male offspring of dams given propylthiouracil at 0.1% in the drinking-water for the first 25 days of their life was increased by about 70%, while luteinizing hormone-stimulated testosterone production and the steroidogenic potential from 22(R)-hydroxycholesterol — measured as testosterone production — were reduced by 55% and 73%, respectively (Hardy et al., 1993). A similar doubling of the number of Leydig cells was reported in 135-day-old male Sprague-Dawley rats made hypothyroid by the addition of 0.1% propylthiouracil to the drinking-water of their dams from parturition through postnatal day 25, in contrast to a lower average volume and steroid production per Leydig cell (Mendis-Handagama & Sharma, 1994). Examination of 1-, 7-, 14- and 21-day-old male rats exposed to 0.1% propylthiouracil in their dams’ drinking-water showed that, while the number of fetal Leydig cells did not differ from that in controls at any age, there was a delay in the appearance of adult-type Leydig cells (11β-hydroxysteroid dehydrogenasepositive cells) at day 21. In parallel with the morphological delay, luteinizing hormone-stimulated androstenedione production from testis in vitro increased from day 14 to day 21 in samples from controls but not in those from propylthiouracil-treated rats (Mendis-Handagama et al., 1998). A decrease in the relative proportion of Leydig cells (identified by morphology and 3β-hydroxysteroid dehydrogenase staining) in interstitial cells were also observed between day 12 and day 16 in propylthiouracil-exposed Wistar rats (Teerds et al., 1998).

Ultrastructural analysis of Sertoli cells provided evidence of an approximate 10-day delay in development in 25-day-old propylthiouracil-treated male rats, including the presence of mitotic Sertoli cells not present in 25-day-old control males (De Franca et al., 1995). The observed effects on Sertoli cell development confirmed earlier work in Wistar rats exposed to 0.1% propylthiouracil in the drinking-water from birth through day 26. The authors found a cessation of proliferation of control Sertoli cells by day 20, as measured by a bromodeoxyuridine-labelling index, whereas propylthiouracil-treated animals had significantly enhanced labelling indices beginning on day 12 and continuing through at least day 26. As a result, there was an 84% increase in the number of Sertoli cells by day 36 (Van Haaster et al., 1992).

In parallel with the delays in Leydig and Sertoli cell development, the development of germ cells was also impaired by neonatal exposure to propylthiouracil. When Sprague-Dawley rats were given 0.1% propylthiouracil in the drinking-water on days 1–25 of postnatal life, decreases in the numbers of spermatocytes and round spermatids were observed at days 20 and 30 in the testes of propylthiouracil-treated rats when compared with controls (Simorangkir et al., 1997).

Further examination of this experimental model of increased testis weight and function after exposure of rats to propylthiouracil during days 1–24 of life indicated that the testis weights were reduced between 10 and 60 days of age, after which time the increase became apparent (Kirby et al., 1992). Serum luteinizing and follicle-stimulating hormone concentrations were reduced to 50–70% of control levels throughout life, the changes being noticeable early after onset of exposure to propylthiouracil. The serum concentrations of growth hormone, prolactin and T4, which were depressed during exposure, returned to control levels at 40–50 days of age — i.e. within a few weeks after cessation of treatment — as did the increase in TSH concentration. The dose–response characteristics of the effect on testes were evaluated in 90-day-old male rats given 0, 0.0004, 0.0015, 0.006, 0.012 or 0.1% propylthiouracil in their drinking-water from birth to postnatal day 25. Both testis weight and daily sperm production were significantly increased at all concentrations. The testis weight reached a plateau and the daily sperm production a peak value at the 0.006% concentration. Maternal water consumption was significantly reduced at 0.1% propylthiouracil during days 1–13 post partum and only slightly reduced at 0.006% (Cooke et al., 1993).

Overall, these data support the conclusion that neonatal hypothyroidism in rats allows a prolonged period of proliferation of Sertoli cells, which ultimately leads to increased numbers of Leydig cells, increased testis weights and increased daily sperm production in adults. While most of the studies were conducted by giving drinking-water containing 0.1% propylthiouracil on days 1–25 of postnatal life, one study suggested that the effects would probably occur at concentrations down to at least 0.0004% propylthiouracil in water.

In order to study the effects of propylthiouracil on prostate weight, the offspring of Sprague-Dawley rats maintained on 0.1% propylthiouracil in the drinking-water from parturition until they were 25 days of age were examined between days 14 and 180. The ventral prostate weights were lower than those of controls up to 95 days of age but increased from day 95, and the glands were about 40% heavier at 180 days of age. The increase in weight was at least partially due to the presence of new ductal structures. The histological appearance of the prostate was normal at all ages, but a transient increase in amiloride-inhibitable plasminogen activator activity was seen in the ventral and dorso-lateral prostate at 42 days of age. These activities had returned to control levels by 90 days. Treatment with propylthiouracil also increased the activity of metalloprotease in the ventral prostate at 21–42 days of age. and in the dorsolateral prostate at 21 and 28 days of age (Wilson et al., 1997).

Examination of female Wistar rats that received 0.1% propylthiouracil in the drinking-water from birth through day 40 indicated that their body weights were significantly reduced by 12 days of age and their ovarian weights by 21 days of age; by day 40, there were signs of altered follicular development. In contrast to effects seen in males, the follicle-stimulating hormone concentration was not reduced in propylthiouracil-treated females (Dijkstra et al., 1996).

Groups of 70–114-day-old female Sprague-Dawley rats were exposed to propylthiouracil in the diet (0.3%) and drinking-water (0.001%) from parturition until their pups were 30 days of age. There were four litters per group. The serum T4 concentrations of the dams were depressed through 120 days of age, and their body weight was diminished by about 20%. Neuroanatomical effects in 90-day-old offspring of treated dams included thinning of the cerebellar cortex and fewer synapses in Purkinje cells. In behavioural assessments which included differential reinforcement of low-rate learning, escape and avoidance tasks and motor activity and exploration, control rats learned the escape and avoidance tasks faster and were hyperactive (Schalock et al., 1977).

The effects of propylthiouracil on heart and kidney development were studied in Sprague-Dawley rats by treating their dams by subcutaneous injection of 20 mg/kg bw from gestation day 17 to lactation day 5, and by direct injection of the pups on postnatal days 1–5. Body and organ weights and organ DNA and protein content were determined in groups of 7–12 animals on multiple days between birth and day 50. Propylthiouracil significantly impaired body growth and heart and kidney weights (by 10–25%), although the weights had returned to control levels by 50 days of age. The changes in the DNA content of these two organs were similar to the body weight effects, recovery taking longer in the kidney than in the heart; cell size was reduced to a greater extent and for longer periods than cell number (Slotkin et al., 1992).

Coronary arterioles were examined in 12-, 28- and 80-day-old Sprague-Dawley rats of dams that had received 0.05% propylthiouracil in their drinking-water on postnatal days 2–28. The body weights of the offspring were significantly depressed after day 20, while their heart rates were significantly depressed at 12 and 28 days of age. Long-term depression of the cardiac mass was also noted, in the presence of capillary proliferation and marked attenuation of arteriolar growth (Heron & Rakusan, 1996).

Female Wistar rats received 0.1% propylthiouracil in the drinking-water from the beginning of gestation through lactation [precise treatment period not indicated], and brain development was evaluated in 6–10 offspring per group on postnatal days 5, 20 and 48. Propylthiouracil significantly reduced the live litter size and pup weight at all ages and also significantly reduced the volume of the neocortex. Further analysis indicated reduced numbers of glial cells in the neocortex only at day 48, while the numbers of neurons were not significantly reduced at any age (Behnam-Rassoli et al., 1991).

The auditory response (brainstem-response audiometry) to frequencies of 4 and 16 kHz was evaluated in Sprague-Dawley rats 12, 16, 25 and 125 days of age that had been exposed to propylthiouracil during various 10-day periods of development. For exposure during gestation, 0.05% propylthiouracil was given in the drinking-water; for exposure after birth, 7 mg/kg bw were given by subcutaneous injection. Hypothyrodism was confirmed by a hormone assay. After neonatal exposure, the concentrations of thyroid hormones were reduced to about 20% of the control levels and that of TSH was about 10-fold higher. The hormone concentrations were not significantly reduced when exposure began at 28 or 120 days of age. Treatment with propylthiouracil significantly increased the latency of wave 1 (representing the cochlear nerve compound action potential) of the brainstem response when given from 3 days before parturition through 6 days of age, but had no permanent effect when given for 10 days starting 10 days after birth (Hébert et al., 1985).

The effects of propylthiouracil on growth, motor development and auditory function were evaluated in Long Evans rats (six to eight litters per group) exposed via the drinking-water to propylthiouracil at 0, 1, 5 or 25 mg/L from gestation day 18 to postnatal day 21. No effects were observed at 1 mg/L. At 5 and 25 mg/L, the serum T4 concentration was sharply reduced on days 1, 7, 14 and 21 after birth, while that of T3 was reduced on days 7, 14 and 21 at 25 mg/L and on day 21 at 5 mg/L. Pups exposed to 25 mg/L had reduced body weights, delayed eye opening, delayed preweaning motor activity and persistent postweaning hyperactivity. Slight effects on eye opening and motor activity were noted at 5 mg/L. Adult offspring that had been exposed to 5 or 25 mg/L showed auditory startle deficits at all frequencies tested (range, 1–40 kHz) (Goldey et al., 1995).

Reproductive development was studied after subcutaneous injection of 0 or 50 mg/kg bw per day propylthiouracil to groups of 10–15 ICR mice from postnatal day 1 until day 28. No effects on growth were seen in the offspring. The plasma T3 concentration was reduced by 40–50% [period not stated]. Histologically, the ovaries of propylthiouracil-treated females showed decreased numbers of primordial, multi-laminar and Graafian follicles as folliculogenesis occurred during days 14–28. In males, there was evidence of reduced numbers of seminiferous tubules, but the histological appearance was normal. The fertility of both male and female treated mice was normal (Chan & Ng, 1995).

Daily exposure by oral gavage to propylthiouracil at 0 or 50 mg/kg bw of groups of six male and female CD rats on days 26–96 affected the growth rates of animals of each sex, altered the estrous cycles of females (with a predominance of diestrous stages), increased the weights of the thyroid, pituitary and testis and decreased the weight of the adrenals (Baksi, 1973).

4.4. Effects on enzyme induction or inhibition and gene expression

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems

Hepatic and renal 5′-deiodinase activities were strongly inhibited in microsomal preparations from male Sprague-Dawley rats that had been given propylthiouracil orally at 10 mg/kg bw per day for 7 or 14 days (de Sandro et al., 1991). The inhibition could be reversed by increasing amounts of glutathione (Yamada et al., 1981).

Propylthiouracil significantly decreased cytochrome c reductase and aniline hydroxylase activity in male Wistar rat microsomes (Raheja et al., 1985).

Propylthiouracil inhibited glutathione transferases in a concentration-dependent manner, a 10-mmol/L concentration causing 25% inhibition. The S-oxides of propylthiouracil were even more potent inhibitors: the 2-sulfonate inhibited the enzyme activity by 80% (Kariya et al., 1986).

Propylthiouracil given at 0.05% in drinking-water for 4 weeks to young and aged male Lewis rats (3 and 26 months, respectively) resulted in increased synaptosomal acetylcholinesterase activity in both groups, an increased density of muscarinic receptor sites in the young rats and an increase in synaptosomal cholesterol concentration in the aged animals (Salvati et al., 1994).

Propylthiouracil increased thyroglobulin mRNA levels in the Fischer rat thyroid cell line FRTL-5 and resulted in accumulation of thyroglobulin in the medium. The total RNA levels were not affected. The effects were suppressed by iodide and did not occur when protein synthesis was inhibited by cycloheximide (Leer et al., 1991).

4.5. Genetic and related effects

4.5.1. Humans

No data were available to the Working Group.

4.5.2. Experimental systems (see Table 1 for references)
Table 1. Genetic and related effects of propylthiouracil.

Table 1

Genetic and related effects of propylthiouracil.

Propylthiouracil did not induce gene mutations in bacteria, or DNA strand breaks in primary cultures of rat or human hepatocytes. It was marginally mutagenic to yeast. Chromosomal aberrations were not induced in a mouse mammary carcinoma-derived cell line or in cultured thyroid cells [not otherwise defined] derived from male Wistar rats given drinking-water containing propylthiouracil at 0.06 mg/L for 10 or 15 weeks. It did not induce somatic recombination in eye cells of Drosophila melanogaster when administered continuously in feed to larvae.

4.6. Mechanistic considerations

There are insufficient data to evaluate the genotoxicity of propylthiouracil.

The main effect of propylthiouracil in humans and rodents is inhibition of thyroid peroxidase, which results in decreased plasma concentrations of T3 and T4 and an increased concentration of TSH, with consequent thyroid follicular-cell proliferation and growth. Squirrel monkeys are much less sensitive to the effect of propylthiouracil on thyroid peroxidase than rats. Another effect of propylthiouracil is inhibition of conversion of T4 to T3 by inhibiting type-1 deiodinase. Alteration of thyroid hormone production is the presumptive mechanism for thyroid tumour formation in rodents.

The lack of adequate data on genotoxicity for propylthiouracil precludes a conclusion regarding the mechanism of carcinogenicity.

5. Summary of Data Reported and Evaluation

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.

5.5. Evaluation

There is inadequate evidence in humans for the carcinogenicity of propylthiouracil.

There is sufficient evidence in experimental animals for the carcinogenicity of propylthiouracil.

Overall evaluation

Propylthiouracil is possibly carcinogenic to humans (Group 2B).

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THIOURACIL

This substance was considered by previous working groups, in 1974 (IARC, 1974) and 1987 (IARC, 1987). Since that time, new data have become available, and these have been incorporated into the monograph and taken into consideration in the present evaluation.

1. Exposure Data

1.1. Chemical and physical data

1.1.1. Nomenclature
  • Chem. Abstr. Serv. Reg. No.: 141-90-2
  • Deleted CAS Reg. Nos: 156-82-1; 4401-53-0; 4401-54-1; 107646-88-8; 107646-89-9
  • Chem. Abstr. Name: 2,3-Dihydro-2-thioxo-4(1H)-pyrimidinone
  • IUPAC Systematic Name: 2-Thiouracil
  • Synonyms: 4-Hydroxy-2-mercaptopyrimidine; 6-hydroxy-2-mercaptopyrimidine; 4-hydroxy-2-pyrimidinethiol; 2-mercapto-4-hydroxypyrimidine; 2-mercapto-4-pyrimidinol; 2-mercapto-4-pyrimidinone
1.1.2. Structural and molecular formulae and relative molecular mass
Image 127a
1.1.3. Chemical and physical properties of the pure substance
1.1.4. Technical products and impurities

Trade names for thiouracil include Antagothyroil, Deracil and Nobilen.

1.1.5. Analysis

Methods have been reported for the analysis of thiouracil in biological fluids (blood, milk, serum, urine), tissues, incubation material, dried animal feed, feed additives and drugs. The methods include potentiometric titration, capillary zone electrophoresis with ultraviolet detection, flow injection analysis with chemiluminescent detection, micellar electrokinetic chromatography, thin-layer chromatography, high-performance thin-layer chromatography, high-performance liquid chromatography (HPLC) with atmospheric pressure chemical ionization mass spectrometry, reversed-phase HPLC with ultraviolet and electrochemical detection and gas chromatography with negative-ion chemical-ionization mass spectrometry (Saldaña Monllor et al., 1980; Moretti et al., 1986; Hooijerink & De Ruig, 1987; Moretti et al., 1988; Centrich Escarpenter & Rubio Hernández, 1990; Watson et al., 1991; De Brabander et al., 1992; López García et al., 1993; Moretti et al., 1993; Vinas et al., 1993; Batjoens et al., 1996; Krivánková et al., 1996; Blanchflower et al., 1997; Le Bizec et al., 1997; Yu et al., 1997; Buick et al., 1998; Vargas et al., 1998; Esteve-Romero et al., 1999; Ciesielski & Zakrzewski, 2000).

1.2. Production

Thiouracil can be prepared by condensing ethyl formylacetate with thiourea (Budavari, 2000).

Information available in 2000 indicated that thiouracil was manufactured by six companies in China and one company in Switzerland (CIS Information Services, 2000).

1.3. Use

Thiouracil was introduced in 1943 as the first thionamide anti-thyroid drug. The usual dose was 1–2 g/day in divided doses. Owing to a high frequency of adverse reactions, especially agranulocytosis, its use was abandoned in favour of other, less toxic drugs, such as propylthiouracil and methimazole (see monographs in this volume). Thiouracil is not currently used as a thyrostatic drug in humans (Astwood & VanderLaan, 1945; Stanley & Astwood, 1949).

Thiouracil also has been reported to be used as a chemical intermediate (IARC, 1974) and in metal plating.

1.4. Occurrence

1.4.1. Occupational exposure

According to the 1981–83 National Occupational Exposure Survey (National Institute for Occupational Safety and Health, 2000), about 1800 technicians and metal-plating machine operators working in the manufacture of instruments and related products were potentially exposed to thiouracil in the USA.

1.4.2. Environmental occurrence

Thiouracil occurs in seeds of Brassica and Cruciferae (Budavari, 2000).

1.5. Regulations and guidelines

No data were available to the Working Group.

2. Studies of Cancer in Humans

No information was available specifically on thiouracil.

2.1. Cohort studies

Dobyns et al. (1974) followed up 34 684 patients treated in England and the USA for hyperthyroidism between 1946 and 1964, 1238 of whom had been treated for at least 1 year with unspecified anti-thyroid drugs. No malignant thyroid neoplasm was found within 1 year of treatment. By 1968, more cases of thyroid neoplasm were found at follow-up among patients initially treated with anti-thyroid drugs (4 malignant tumours and 18 adenomas in 1238 patients) than among those initially treated with 131I (19 malignant tumours and 41 adenomas in 21 714 patients) or (partial) thyroidectomy (4 malignant tumours and 14 adenomas in 11 732 patients). The authors suggested that more neoplasms were found in the drug-treated patients because subsequent thyroidectomy was more frequent in this group (30% of drug-treated patients, as compared with 0.5% of those initially treated with 131I and 1.2% of those treated with primary thyroidectomy), which provided more opportunity for identification of neoplasms. [The Working Group noted that rates could not be calculated because person–years were not provided, and the ages of the groups were not given.]

Ron et al. (1998) updated the report of Dobyns et al. (1974) and followed-up 35 593 patients treated for hyperthyroidism between 1946 and 1964 in 25 clinics in the USA and one in the United Kingdom. By December 1990, about 19% had been lost to follow-up, and 50.5% of the study cohort had died. A total of 1374 patients (1094 women) had been treated with anti-thyroid drugs only, 10 439 (7999 women) with 131I and drugs, 10 381 (8465 women) with thyroidectomy and drugs, 2661 (2235 women) with a combination of the three types of treatment and the remainder by other means. The drugs used during the study period were chiefly thiourea derivatives and iodine compounds. One year or more after the start of the study, the standardized mortality ratio (SMR) in comparison with the general population for the patients treated with anti-thyroid drugs only was 1.3 (95% confidence interval [CI], 1.1–1.6) for deaths from all cancers, which was chiefly due to significantly more deaths from oral cancer (4.2; 95% CI, 1.3–9.7; five cases) and brain tumours (3.7; 95% CI, 1.2–8.6; five cases). The excess risk for death from brain cancer persisted after exclusion of cases prevalent at the time of entry into the study. No deaths from thyroid carcinoma were recorded. The SMR for all cancers was approximately 1.0 in patients treated with 131I or surgery (with or without anti-thyroid drugs), but the SMR for thyroid cancer was fourfold higher (3.9; 95% CI, 2.5–5.9; 24 cases observed) among patients who had been treated with 131I with or without drugs. The authors noted that the group treated with drugs only was small; the type, quantity and dates of drug use were generally not available; and many patients had cancer before entry into the study, suggesting that some, but not all, of the excess could be attributed to the selection of patients with health problems for drug therapy. [The Working Group noted that the expected number of deaths from thyroid carcinomas was not reported, although it would almost certainly have been less than 1.0. Results were given separately for patients treated only with drugs and not for those given drugs with other treatment.]

2.2. Case–control studies

Ron et al. (1987) conducted a study of 159 cases of thyroid cancer and 285 population controls in Connecticut, USA, between 1978 and 1980. The use of anti-thyroid medications was not associated with an increased risk [relative risks not shown].

In a study carried out in northern Sweden between 1980 and 1989, 180 cases of thyroid cancer and 360 population controls were evaluated (Hallquist et al., 1994). Use of anti-thyroid drugs (two cases and two controls) was associated with a relative risk of 2.0 (95% CI, 0.2–21).

3. Studies of Cancer in Experimental Animals

Thiouracil was evaluated in a previous monograph (IARC, 1974). Because there have been no new studies on its carcinogenicity in animals, the most relevant studies from the previous monograph were analysed in greater depth. One study in which thiouracil was administered with a known carcinogen which had been published since the previous evaluation is summarized. Studies on the carcinogenicity of anti-thyroid chemicals, including thiouracil, in experimental animals have been reviewed (Doniach, 1970; Christov & Raichev, 1972; Paynter et al., 1988).

3.1. Oral administration

Mouse: Groups of 28 A, 29 C57 and 24 I mice [sex unspecified], 1–3 months of age, were fed diets containing thiouracil [purity not specified] at a concentration of 0.1% for various periods up to 81 weeks. Groups of 36 untreated A, 51 untreated C57 and 35 untreated I mice served as controls. In 69 treated mice of all three strains examined at various intervals, the author described thyroid follicular-cell hyperplasia from 40 days of treatment, which developed into follicular cystic or nodular lesions after 180 days. The author interpreted these lesions as non-malignant. In seven treated A strain mice, pulmonary foci very similar to the hyperplastic thyroid tissue were present (Gorbman, 1947). [The Working Group considered that, under current histopathological criteria, the thyroid and pulmonary lesions described in the study might be diagnosed as thyroid neoplasia and metastases of thyroid neoplasia.]

A total of 143 female C3H mice, approximately 10 weeks of age, were divided into two approximately equal groups; one was fed basal diet and served as controls, and the other received thiouracil in the diet at an initial concentration of 0.375%, increased later to 0.5%. The animals were killed at selected intervals or when moribund. The authors described the development of thyroid follicular-cell hyperplasia in treated mice during the first 12 months of the study but diagnosed no neoplasia. However, 10/23 mice treated for 362–464 days developed pulmonary metastases of thyroid tissue, which were interpreted by the authors as ‘benign metastasizing thyroid tissue’ (Dalton et al., 1948). [The Working Group noted that, under current histopathological criteria, the pulmonary lesions might be regarded as metastases of thyroid neoplasia.]

Groups of male and female C3H mice and an inbred strain designated TM [initial numbers not specified], 1 month of age, were fed a diet containing 0.3% thiouracil [purity not specified] for 17 months. Thiouracil produced ‘hepatomas’ in 12/13 male and 14/16 female C3H mice but not in 22 male or 22 female TM mice. In the control groups, hepatomas occurred in 2/32 male and 0/24 female C3H mice and in 0/20 male and 0/20 female TM mice (Casas, 1963).

Rat: Groups of 6–20 male and 7–15 female Stanford albino rats, of an average age of 55 and 45 days, respectively, were fed diets containing thiouracil [purity not specified] at a concentration of 0.1% for various periods from 120 up to 312 days. Nodular hyperplasia (solitary or multiple nodules) of the thyroid was observed in 20/56 male rats examined at 169 days and in 17/55 female rats examined at 120 days. The nodular lesions were considered by the author to be benign (Laqueur, 1949). [The Working Group noted the lack of a control group.]

In a study of the combined effects of thiouracil and 2-acetylaminofluorene on the thyroid gland, 20 male and female Sherman strain rats, weighing 75–100 g [age not specified], were given thiouracil [purity not specified] in the drinking-water at a concentration of 0.05 or 0.1% for 245–884 days. Thyroid tumours occurred in 12/20 rats [not separated on the basis of dose], 11 of which had adenomas and one a carcinoma. In the group receiving thiouracil and 0.03% 2-acetylaminofluorene in the diet simultaneously and killed after only 22–45 weeks, the incidences of thyroid follicular-cell adenomas and carcinomas were 28/28 and 5/28, respectively (Paschkis et al., 1948). [The Working Group noted that there was no untreated control group.]

A group of 35 male Sprague-Dawley rats, weighing on average 61 g [age not specified], was given thiouracil [purity not specified] in the drinking-water at a concentration of 0.2% for 24 months. A control group of 25 males was available. Two rats from each group were killed at 6, 14 and 18 months, and the remaining 26 treated and 17 control rats were killed at 2 years. Thyroid adenomas were diagnosed in approximately 65% of the treated rats, but the tumour incidence in the control group was not reported (Clausen, 1954). [The Working Group noted the limited information provided in the report.]

In a complex study of carcinogen interactions in various target organs, groups of 23–24 male and female Fischer 344 rats [age not specified] were fed diets containing thiouracil [‘checked for purity’] at a concentration of 83, 250 or 750 mg/kg for 104 weeks. A control group comprised 214 male and 214 female rats. At 725 days, the numbers of survivors were 191/214, 19/24, 21/24 and 4/24 males at 0, 83, 250 and 750 mg/kg, respectively, and 184/214, 21/23, 18/24 and 17/24 females, respectively. The incidences of malignant thyroid follicular-cell tumours over the study period were 5/214, 6/24, 14/24 and 5/24 males and 5/214, 2/23, 6/24 and 18/24 females in the four groups, respectively. No malignant liver or kidney tumours were found (Fears et al., 1989).

3.2. Administration with known carcinogens

Gerbil: Groups of 20 male and 11 female gerbils [age not specified but stated as equal across groups] were given diets containing thiouracil [purity not specified] at a concentration of 0.2% in combination with a subcutaneous injection of 23 mg/kg bw N-nitrosodiethylamine (NDEA) once a week for life. Additional groups of 20 males and 19 females received NDEA only, and 12 males and 12 females received the thiouracil diet only; a vehicle control group of 11 males and 10 females received 0.9% saline only. The average survival times were 37 weeks for males and 24 weeks for females given NDEA only, 54 weeks for males and 45 weeks for females given NDEA plus thiouracil, 79 weeks for males and 81 weeks for females given thiouracil only and 80 weeks for males and 69 weeks for females given saline. Thiouracil given in conjunction with NDEA inhibited the development of cholangiocarcinomas induced by NDEA alone, the incidences being 17/20 males and 16/19 females given NDEA only and 0/20 males and 0/11 females given NDEA plus thiouracil. Some cholangiomas were also observed, the incidences being 0/20 males and 0/19 females given NDEA only and 13/20 males and 4/11 females given NDEA plus thiouracil. The incidence of nasal cavity adenocarcinomas induced by NDEA was not influenced by thiouracil, and no tumours of any type were observed in the group given thiouracil alone (Green & Ketkar, 1978).

4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms

4.1. Absorption, distribution, metabolism and excretion

4.1.1. Humans

No data were available to the Working Group.

4.1.2. Experimental systems

In male Sprague-Dawley rats given a single intraperitoneal injection of 5 mg of [35S]thiouracil, thyroid accumulation of the label began at 4 h and reached a peak at 10 h. The concentration gradient between thyroid tissue and plasma was 7.5 at 10 h and 156 after 48 h. Five 35S-labelled compounds were detected in the thyroid by thin-layer chromatography: [35S]sulfate, protein-bound 35S, unmetabolized thiouracil and two unidentified metabolites (Lees et al., 1973). Accumulation of [35S]thiouracil in the thyroid of rats was also reported by Marchant et al. (1972).

Rapid placental transfer of [14C]thiouracil was demonstrated in rabbits given a single intravenous injection of 0.01–0.03 mmol [1.3–3.8 mg] on days 31–33 of gestation and in dogs injected with a dose of 0.05 mmol [6.4 mg] on days 61–63 of gestation. An equilibrium was reached between maternal and fetal blood within 30 min, but the concentrations in maternal and fetal thyroid increased for 3 and 6 h after treatment in rabbits and dogs, respectively. The radiolabel in the fetal thyroid appeared to be associated with the parent compound (Quinones et al., 1972).

After intraperitoneal injection of [14C]thiouracil to pregnant Sprague-Dawley rats on day 10, 12, 14, 17 or 20 of gestation, placental transfer was found at all stages but was most pronounced at late stages of gestation (Sabbagha & Hayashi, 1969).

Autoradiographic analysis of the fate of about 0.07 mg of [14C]thiouracil injected intravenously into pregnant NMRI mice in a late stage of gestation [gestational age not indicated] revealed accumulation in the fetal thyroid (Slanina et al., 1973).

4.2. Toxic effects

4.2.1. Humans

When thiouracil was used as an anti-thyroid drug, a high frequency of adverse reactions was seen (VanderLaan & Storrie, 1955), including agranulocytosis.

4.2.2. Experimental systems

Thiouracil increased the iodide content of the salivary glands and decreased that of the thyroid of white male rats [strain not specified] fed a diet containing 0.035% thiouracil for 3 months (Hassanein & Almallah, 1978).

Male Fischer rats fed a low-iodine diet containing 0.25% thiouracil developed hyperplasia of the thyroid gland within 3 days, and the capsule of the gland increased to a substantial multilayered structure (Wollmann & Herveg, 1978).

Enlargement of the adipose tissue pads on the thyroid of male Fischer rats during ingestion of a diet containing 0.25% thiouracil for 10 days was probably due to an elevated concentration of circulating thyroid-stimulating hormone and not to a direct effect of thiouracil (Smeds & Wollman, 1983).

4.3. Reproductive and developmental effects

4.3.1. Humans

No data were available to the Working Group.

4.3.2. Experimental systems

Perinatal thyroid deficiency induced by thiouracil (2 mg/kg of diet) given to pregnant rats [strain not specified] during the last 15 days of gestation and the first 15 days after parturition caused a chronic hypermetabolic state in both male and female offspring. In female rats, a mild hyperthyroid condition occasionally persisted (Davenport & Hennies, 1976).

The adrenal weights of 15-day-old Sprague-Dawley rats made hypothyroid by administration of 0.25% thiouracil in the diet of dams from the day of conception through lactation were reduced by 23%, but they showed no change in adrenal corticosterone secretion or corticosterone secretion per milligram of adrenal tissue. The corticotropin-releasing factor-like activity of the median eminence was reduced (Meserve & Pearlmutter, 1983). A similar response was observed in genetically hypothyroid (hyt/hyt) mice born to heterozygous dams, but the effect was not apparent until 30 days of age, i.e. after weaning, suggesting a role of maternal thyroid hormones in the maintenance of hypothalamic corticotropin-releasing factor (Meserve, 1987). A time-course study of corticosterone release after corticosterone stimulation in 15-day-old Sprague-Dawley rats made hypothyroid by dietary exposure of the dams to 0.25% thiouracil from conception indicated that the hypothalamic response was attenuated and not ablated (Meserve & Juárez de Ku, 1993).

4.4. Effects on enzyme induction or inhibition and gene expression

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems

In male CD rats given an intraperitoneal injection of 10–50 mg/kg bw thiouracil, in the absence of oxidizable substrates, irreversible inhibition of thyroid iodide peroxidase occurred. When iodine or thiocyanate was present, the inhibition was prevented, suggesting that the initial action of thiouracil is to block iodination by trapping oxidized iodide (Davidson et al., 1978).

Female Sprague-Dawley rats fed a diet containing 0.2% thiouracil for 14 days had increased (approximately threefold) NADH duroquinone (2,3,5,6-tetramethyl-1,4-benzoquinone) reductase activity and decreased (by ∼ 20%) α-glycerophosphate dehydrogenase activity compared with controls (Ruzicka & Rose, 1981).

Chopra et al. (1982) studied the structure–activity relationships of the inhibition of hepatic monodeiodination of thyroxine to triiodothyronine by thiouracil and other related compounds in liver homogenates from male Sprague-Dawley rats. The results suggested that the thiourea moiety is insufficient to inhibit the conversion.

In rat liver microsomal systems, thiouracil at 0.5 or 1 µmol/L [64 or 128 µg/L] was a non-competitive inhibitor with respect to substrate and a competitive inhibitor with respect to cofactors of iodothyronine-5′-deiodinase (Visser, 1979). Inactivation of iodothyronine-5′-deiodinase by thiouracil required a substrate (Visser & van Overmeeren-Kaptein, 1981).

Thiouracil inhibited peroxidase in a microsomal preparation from the gastric mucosa of male Swiss mice (Banerjee & Datta, 1981).

4.5. Genetic and related effects

4.5.1. Humans

No data were available to the Working Group.

4.5.2. Experimental systems (see Table 1 for reference)
Table 1. Genetic and related effects of thiouracil.

Table 1

Genetic and related effects of thiouracil.

Thiouracil did not induce DNA strand breaks in cultured mammalian cells in the only study in which thiouracil was tested alone for genotoxicity.

Irradiation of Escherichia coli recA− cells in the presence of thiouracil resulted in greater cytotoxicity than in wild-type or uvrA− cells. Furthermore, thiouracil enhanced the incidence of mutations induced by ultraviolet A irradiation in E. coli uvrA−, but not recA− cells, while irradiation of Salmonella cells with ultraviolet A in the presence of thiouracil led to increased expression of umuDC (Komeda et al., 1997). Thiouracil enhanced the DNA-strand breaking effect of 334-nm ultraviolet radiation in purified bacterial DNA (Peak et al., 1984).

4.6. Mechanistic considerations

Thiouracil belongs to a class of drugs used in the treatment of hyperthyroidism which act by interfering with thyroid peroxidase functioning, thus decreasing thyroid hormone production and increasing proliferation by increasing the concentration of thyroid-stimulating hormone. This is the probable basis of the tumorigenic activity of thiouracil in the thyroid of experimental animals.

The lack of adequate data on genotoxicity for thiouracil precludes a conclusion regarding the mechanism of carcinogenicity.

5. Summary of Data Reported and Evaluation

5.1. Exposure data

Thiouracil was used briefly in the 1940s as the first thionamide anti-thyroid drug.

5.2. Human carcinogenicity studies

No epidemiological data on use of thiouracil 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

Several early studies in mice showed that oral administration of thiouracil induced nodular thyroid follicular-cell hyperplasia, including some pulmonary metastases suggestive of thyroid neoplasia by current histopathological criteria. In one study in one strain of mice, thiouracil produced hepatocellular tumours. In one adequate study in rats, thiouracil produced thyroid follicular-cell adenomas and carcinomas. In one study in gerbils, thiouracil inhibited the progression of N-nitrosodiethylamine-induced cholangiomas into cholangiocarcinomas.

5.4. Other relevant data

Little is known about the disposition of thiouracil in humans. In rats and fetal rats, thiouracil accumulated in the thyroid. Thiouracil acts by inhibiting thyroid peroxidase, thus decreasing thyroid hormone production, and it increases proliferation by increasing the secretion of thyroid-stimulating hormone. This is the probable basis of its tumorigenic activity in the thyroid of experimental animals.

No data were available on the developmental or reproductive effects of thiouracil in humans. The only studies in experimental animals indicated altered adrenal function in young rats made hypothyroidal from birth.

In the only study in which thiouracil was tested for genotoxicity, it did not induce DNA strand breaks in cultured mammalian cells. It has not been tested for mutagenicity or clastogenicity.

5.5. Evaluation

There is inadequate evidence in humans for the carcinogenicity of thiouracil.

There is sufficient evidence in experimental animals for the carcinogenicity of thiouracil.

Overall evaluation

Thiouracil is possibly carcinogenic to humans (Group 2B).

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