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Your Location:Home > Thiourea effect on laboratory mammals and in vitro test systems

For more details on the studies in this section, the reader is referred to MAK (1988).

Single exposure

The acute toxicity of thiourea varies with the species, strain, and age of the animals exposed to the chemical and with the iodine content of their diet. Oral LD50s are about 1000 mg/kg body weight for mice, 125–1930 mg/kg body weight for rats, depending on the strain, and 10 000 mg/kg body weight for rabbits. The intraperitoneal LD50 for the rat ranges between 4 and 1340 mg/kg body weight, according to the strain. Death at these doses is due to lung oedema, and the survivors exhibit pleural effusion. Accordingly, thiourea at doses between 10 and 500 mg/kg body weight has been employed in experimental animal studies as a model agent for the elicitation of lung oedema and pleural effusion. The pathological effects are prevented by pretreatment of the animals with cysteine or glutathione, which reduces the irreversible binding of radioactivity to lung proteins after administration of [14C]thiourea. Toxic doses of thiourea also resulted in hyperglycaemia, glucosuria, polyuria, and a reduction in the liver glycogen level in rats (MAK, 1988).

The LC50 of a 10% aqueous solution for rats (4 h of inhalation) is above 195 mg/m3 (TNO, 1979b). The dermal LD50 for New Zealand White rabbits is above 2800 mg/kg body weight. Thiourea was applied on the shaved skin as solutions in water in amounts of 9 ml/kg body weight for each dose level (TNO, 1978).

An intraperitoneal dose of thiourea in male Sprague-Dawley rats (10 mg/kg body weight) resulted in significant elevations in plasma histamine as well as in lung vascular permeability and 100% mortality within 24 h. A non-lethal dose (0.5 mg/kg body weight) given as pretreatment followed by the lethal dose at 1, 4, 8, 16, and 32 days provided complete protection against death for 8 days and partial protection until 24 days. This decrease in mortality correlated quite closely with reduced plasma histamine levels and diminished pulmonary vascular permeability. The authors concluded that the degree of tolerance to thiourea developed is related to plasma histamine concentration and pulmonary vascular permeability (Giri et al., 1991b).

Experimental pulmonary oedema was induced in adult male Sprague-Dawley rats injected intraperitoneally with thiourea at doses of 3, 6, or 10 mg/kg body weight. Induction of pulmonary oedema was observed by a significant increase in the ratio of lung weight to body weight in all three groups of experimental rats. An increase in plasma calcium and a decrease in plasma copper and ceruloplasmin were observed in the rats in the two highest dose groups (Sarkar et al., 1988).

Irritation and sensitization

A 24-h exposure to undiluted thiourea applied to the intact and abraded skin of rabbits resulted in mild to marked erythema with a slight degree of oedema (TNO, 1983a). When rabbit skin was exposed to 0.5 g of thiourea for a period of 4 h, the substance was tolerated without reaction (Korte & Greim, 1981).

A single application of a 10% (w/w) aqueous solution of thiourea to the eye was tolerated without reaction (TNO, 1983b). In another study, the application of 100 mg thiourea to the conjunctiva of the rabbit eye resulted in reddening (1–2 using Draize scoring) and swelling (1–2 using Draize scoring) (Korte & Greim, 1981).

Thiourea yielded negative results in a sensitization test carried out with guinea-pigs according to the method of Magnusson & Kligman (1970) (Korte & Greim, 1981).

Short-term exposure

When 28-day-old male rats (strain not given) were treated daily for 2 weeks with thiourea administered at 600 ± 60 mg/kg body weight via gastric intubation, about a 50% reduction of body weight gain was observed (Smith, 1950). Daily ingestion of 131 mg thiourea/kg body weight in drinking-water by 21- to 30-day-old female rats (strain not given) for 10 consecutive days led to hyperplasia of the thyroid, which could be demonstrated both macroscopically and microscopically. No such effect resulted from treatment with 12 mg thiourea/kg body weight (Astwood, 1943). Another study demonstrated a reduction of the basal metabolic rate, which could be prevented by simultaneous administration of thyroxine (tetraiodothyronine, or T4) (MacKenzie & MacKenzie, 1943). Rats received, over a 2-week period, 0.05% thiourea (25 mg/kg body weight per day) up to 2% thiourea (1000 mg/kg body weight per day) in food. The weight of the thyroid glands was increased maximally in rats that received 0.5% thiourea (250 mg/kg body weight per day); the basal metabolic rate showed a definite depression in rats receiving 1% thiourea (500 mg/kg body weight per day). The basal metabolic rate was determined in rats that were starved for 20 h (no further details are given).

The iodine level of the thyroid gland was reduced from 73 to 13 mg/100 g tissue upon the oral administration of thiourea at 70 mg/kg body weight for 10 days (Astwood et al., 1945). Thiourea also resulted in a reduction of thyroid iodine uptake when administered in rats at 1% (500 mg/kg body weight per day) in the diet for 2 months (Keston et al., 1944). Concomitant with reduced thyroid activity, the weight of the pituitary gland increased and signs of pituitary overactivity were evident both histologically and biochemically; the weights of the ovary, uterus, and prostate gland all declined. Haemosiderosis in the spleen, lymph nodes, and intestinal villi of rats was observed subsequent to the administration of 16–50 daily doses of 1 ml of a 1% aqueous solution of thiourea by gavage. The repeated administration of high doses (no quantitative data given) of thiourea in the diet, in the drinking-water, or by intraperitoneal injection resulted in manifold effects: reduced osmotic resistance of the erythrocytes, congestion, haemosiderosis and atrophy of the spleen, anaemia, leukocytopenia, granulocytopenia, increased erythropoiesis in the bone marrow, reduced clotting times, and increased phospholipid levels of the blood (MAK, 1988).

Mice appear to be less sensitive to thiourea than rats, in that daily subcutaneous administration at 500 mg/kg body weight for 10 days resulted in only a slight reduction in the colloid content of the thyroid (Jones, 1946).

Medium-term exposure

When 0.25% thiourea (350 mg/kg body weight per day) was administered to rats in the drinking-water for 65–122 days, an enlargement of the pituitary gland was observed, in addition to structural changes in the pars intermedia, hyperplasia of the parathyroid gland, and fibrotic inflammation of the bones (Malcolm et al., 1949).

Thiourea was administered to Sprague-Dawley rats (10 per sex per dose group) at concentrations of 0, 0.02, 0.1, 0.5, or 2.5 mg/litre (0, 0.0028, 0.014, 0.070, or 0.350 mg/kg body weight per day) in the drinking-water for 13 weeks (Hazleton, 1987). Animals were observed for mortality and moribundity and for overt signs of toxicity. Detailed physical examinations and individual body weight and food consumption measurements were performed. Clinical pathology parameters (haematology, clinical chemistry, urinalysis, triiodothyronine [T3], T4, and TSH levels in blood) were evaluated. There was no evidence of substance-related clinical or histopathological effects.

In mice, no effect on body weight was observed upon inclusion of 2.5 g thiourea/kg in the diet (125 mg/kg body weight per day) for 13 weeks (Morris et al., 1946).

Twenty-seven female lambs (2–3 months old) were orally administered 0 or 50 mg thiourea/kg body weight daily for 2, 4, or 6 months (six treated and three controls per group) (Nasseri & Prasad, 1987a; see section 8.7.2). Slight to moderate facial oedema, significant reduction in weight gain, stunted growth, weakness, profound depression, and loss of appetite were observed. Alopecia became evident from the second month on. The thyroid gland was moderately to severely enlarged, although there was no direct correlation with length of dosing. Muscular weakness and difficulty standing and walking were noted with increased dosing. Hypoglycaemia, hyperlipidaemia/hypercholesterolaemia, and a significant fall in serum T4 were related to length of treatment.

Eight male lambs aged 3–3.5 months were orally administered 50 mg thiourea/kg body weight daily for 3.5 months together with four control lambs (Sokkar et al., 2000; see section 8.7.2). The dosed animals became weak, emaciated, anaemic, and significantly reduced in body weight, with facial oedema and alopecia at thigh, legs, and abdomen. Clinical analysis showed significant reduction in erythrocyte and leukocyte numbers and in levels of T3 and testosterone at the end of the experiment. Histopathology of the thyroid gland revealed hyperplasia of the follicle-lining epithelial cells that project into the lumen. The lumina were devoid of colloid. The testes showed ill developed, small, empty seminiferous tubules. Hepatocytes in the liver showed degeneration and vacuolation with proliferation of Kupffer cells. The kidney showed glomerular lipidosis with accumulation of haemosiderin pigment in the cytoplasm of the renal tubules. Hyperkeratosis of the epidermis was associated with excessive keratin formation within the hair follicles.

Long-term exposure and carcinogenicity

In a chronic toxicity study, thiourea was administered daily in drinking-water at concentrations of 1.72, 6.88, or 27.5 mg/kg body weight to mice for 2 years and to rats for the duration of their lifetimes or a maximum of 3 years. A reduction in body weight gain and an enlargement of the thyroid gland were observed only in the rats in the highest dose group, and no other changes were detected, either macroscopically or microscopically (Hartzell, 1942, 1945). A lowest-observed-adverse-effect level (LOAEL) of 27.5 mg/kg body weight per day (reduction of body weight and enlargement of thyroid gland) and a no-observed-adverse-effect level (NOAEL) of 6.88 mg/kg body weight per day for rats can be given.

Thiourea has not been tested in a standard bioassay of carcinogenicity in rodents. Several older carcinogenicity studies were carried out prior to the mid-1960s (Table 4). They described the occurrence of tumours at numerous locations other than the thyroid gland, but the distribution of these varied from one study to another. Unfortunately, most of these reports are highly unsatisfactory. They lack important details regarding dosages or the frequencies of spontaneous tumour formation, and the doses administered were often sufficiently toxic to result in 100% mortality (IARC, 1974, 2001). In several studies involving different strains of mice, thyroid hyperplasia, but not thyroid tumours, was reported after oral administration. In rats given thiourea orally, a high incidence of thyroid follicular cell adenomas and carcinomas and increased incidences of hepatocellular adenomas and tumours of the Zymbal or Meibomian gland were reported (IARC, 1974, 2001).

Initiation–promotion studies

In an experiment in which thiourea (3 × 200 mg/kg body weight) given in water by gavage was followed by 2 × 10 mg of a technical mixture of polychlorinated biphenyls (PCBs) ("promoter") weekly for 11 weeks in Sprague-Dawley rats, thiourea demonstrated no initiation capacity, as expressed by the number or size of ATP-free islets in the liver. Similarly, when thiourea (0.2% in drinking-water for 12 weeks) was administered after a dose of 8 mg diethylnitrosamine/kg ("initiator"), it expressed no "promotion" activity in the liver (Oesterle & Deml, 1988).

Male F344 rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) at 2000 mg/kg body weight in a single subcutaneous injection were given a diet containing 0 or 0.1% thiourea from weeks 2 to 20 for 19 weeks. Histopathological examination revealed altered hepatocellular foci and/or hepatocellular adenomas in the rats in incidences of 40% and 93% in control and treated rats, respectively. In addition, proliferative lesions in the thyroid consisting of adenomatous nodules and neoplasias and proliferative lesions in the lung were seen in the rats that received thiourea (Shimo et al., 1994b).

In a study with male 4-week-old Fischer 344 rats, 0.1% thiourea was given to them in the drinking-water starting 1 week after they had received a single subcutaneous dose of 2000 mg DHPN/kg body weight. Animals were sacrificed at weeks 1, 2, 4, 8, 12, or 16. Serum T4 levels were decreased by approximately 60% at week 1 and remained significantly lower than in rats treated with DHPN only throughout the experiment, while serum TSH levels were elevated and peaked at 4 weeks (20-fold increase), returning to normal at 12 weeks. Thyroid weights were significantly increased. Hyperplasia was observed at 2 weeks, and adenomas were observed at 4 weeks. Proliferation was greatest when TSH levels were elevated. In 5 of 20 rats treated with DHPN and thiourea, thyroid follicular cell adenomas occurred. In contrast, no tumours were induced in rats treated with DHPN alone (Shimo et al., 1994a).

In a study in which male Fischer 344 rats were given 0.2% thiourea in the drinking-water for 10 weeks, starting 1 week after initial subcutaneous application of DHPN at 2800 mg/kg body weight, the treated animals showed decreased body weights, 5-fold increased thyroid weights, 25% decreased T4 levels, and 5-fold increased TSH levels. Administration of thiourea induced an increased incidence (P < 0.01) of thyroid follicular cell tumours: 10/10 in the DHPN and thiourea group compared with 1/10 in the DHPN-only group (Takegawa et al., 1997).

A further study (Mitsumori et al., 1996) confirmed that thiourea, given after DHPN, increased the frequency of thyroid follicular cell tumours in Fischer rats and showed that this increase was observed for tumours with both adenomatous and solid growth patterns. A single subcutaneous injection of 2.8 g DHPN/kg body weight followed by thiourea at a concentration of 0.2% (280 mg/kg body weight per day) in the drinking-water for 19 weeks increased the incidence of thyroid follicular cell neoplasms in rats after 20 weeks, when the study was terminated.

In summary, it has been shown that thiourea can promote thyroid follicular cell tumours initiated by DHPN.

Genotoxicity and related end-points

Thiourea has been tested in numerous assays. It did not induce gene mutations in bacteria. Inconsistent results, the majority of which were negative, were obtained in mammalian cells. Thiourea induced chromosomal recombination in yeast and insects. Thiourea is not considered to be a genotoxic carcinogen.

Genotoxicity in vitro

Several research groups have investigated the effect of thiourea on Salmonella typhimurium strains TA 97, TA 98, TA 100, and TA 1535 in both the absence and presence of a metabolic activation system. Yamaguchi (1980) reported the doubling of a number of revertants in strain TA 100 at 100 μg thiourea/plate. However, all other authors found no positive effects due to this chemical.

Thiourea tested in the SOS chromotest at concentrations ranging between 7.6 ng/ml and 7.6 mg/ml with a 2-h incubation period both with and without metabolic activation did not induce an increase in the revertants (Brams et al., 1987).

In the umu-test with S. typhimurium strain TA 1535/pSK1002, thiourea was not found to be genotoxic in either the absence or presence of metabolic activation, even at the highest applied concentration of 1670 μg/ml (Nakamura et al., 1987).

Thiourea was tested for its genotoxic potential with Saccharomyces cerevisiae at concentrations of 0, 5, 10, 20, and 40 mg/ml (Schiestl, 1989; Galli & Schiestl, 1996). Deletion and intrachromosomal recombinations were observed to be induced at the two highest concentrations. These concentrations (20 and 40 mg/ml) of thiourea also proved to be highly cytotoxic to the yeast cells, with only 11 and and 1% surviving, respectively. In another study, the application of 0.12–0.4 mol thiourea/litre (about 9.1–30.4 mg/ml) to S. cerevisiae D7 resulted in a 1.5- to 7.5-fold increase in gene conversion at the trp locus over that of the control organisms (Jiang et al., 1989). The effect of thiourea on the permeable yeast mutant S. cerevisiae C658-k42 at concentrations of 0, 0.5, 1.0, and 2.0 mg/ml was tested in both the absence and presence of metabolic activation. Whereas only negative results were obtained without metabolic activation, with it, the concentrations of 0.5 and 1.0 mg/ml led to 6.7- and 4.5-fold increases in trp+ revertants, respectively, in comparison with the control. The concentration of 2.0 mg/ml proved to be ineffective in this regard. The cytotoxicity was less than 15% (Morita et al., 1989).

The genotoxicity of thiourea was investigated with Aspergillus nidulans using concentrations of 65.7–197.1 mmol/litre of the chemical at 99% purity in tests in both the absence and presence of metabolic activation (Crebelli et al., 1986). Neither forward mutations nor chromosomal malsegregations were observed to result from thiourea treatment, although the higher doses of the chemical were generally toxic.

A concentration of 60 mmol thiourea/litre inhibited DNA synthesis in human fibroblasts in the so-called "DNA synthesis inhibition test" (Painter, 1977). Yanagisawa et al. (1987) considered this to be evidence for a genotoxic effect of the chemical.

Thiourea at concentrations of 10–40 mmol/litre induced a 5-fold increase in the frequency of azaguanine-resistant V79 Chinese hamster cells (while the cytotoxicity was less than 15%) in the absence of a metabolic activation system (Ziegler-Skylakakis et al., 1985).

Two studies on the effect of thiourea on L5178Y mouse lymphoma cells in tests in both the presence and the absence of a metabolic activation system (S9-mix from Aroclor 1254-induced rat liver) have been carried out. In one (Caspary et al., 1988), the tests were carried out by two independent contract institutes (A and B), which used similar protocols, in which thiourea concentrations of 0–5000 μg/ml and 0–6000 μg/ml were tested without and with metabolic activation, respectively. The chemical was shown to be non-genotoxic and non-toxic by both institutes in the test without metabolic activation and by institute A in the presence of the metabolic activation system. However, institute B found thiourea to have a positive effect in the test with metabolic activation, although no data on toxicity were provided. Overall, the effect of the chemical was described as being negative in one case (institute A) and positive in the other (institute B). In the second study (Wangenheim & Bolcsfoldi, 1988), thiourea was tested at concentrations of 0, 0.068, 1.37, 2.05, and 2.74 mg/ml in the absence of metabolic activation and at concentrations of 0, 0.63, 0.95, 1.26, 1.89, and 2.52 mg/ml in the presence of the S9-mix. The mutation frequency in the tests without metabolic activation increased 1.3-fold in comparison with the control at the concentrations of 1.37 and 2.05 mg/ml and increased 1.8-fold at 2.74 mg/ml (P < 0.001). The cytotoxicity at these concentrations was estimated to be between 30 and 60%. The corresponding increase at the highest tested concentration with metabolic activation (2.52 mg/ml) was 1.6-fold (P < 0.001). The investigators considered that a positive effect was detectable only by means of statistical evaluation and deemed that a 2-fold or higher mutation frequency would represent a suitable criterion for an unequivocally positive effect. Thiourea was thus concluded to be only weakly mutagenic in this study.

Genotoxicity in vivo

When rats were treated with two successive oral doses of 350 mg thiourea/kg body weight (corresponding to 20% of the LD50; the second oral dose was administered 24 h after the first), no positive results were obtained in a micronucleus test. No symptoms of toxicity or any cytotoxic effects resulted from the treatment (TNO, 1979c).

Seiler (1977) found no inhibition of the incorporation of [3H]thymidine into testicular DNA due to thiourea in vivo using the Friedman-Staub test (Friedman & Staub, 1976).

Thiourea in concentrations of 0.5 and 1.0 mmol/litre nutrient solution had a positive effect in the zeste-white test system of Drosophila melanogaster, whereas equivocal results were obtained with the same concentrations in the white-ivory test system (Batiste-Alentorn et al., 1991, 1994). In the eye mosaic assay with D. melanogaster, the application of 0.5 mmol thiourea/litre yielded positive results with respect to end-point interchromosomal mitotic recombination, whereas the concentration of 1.0 mmol/litre proved to be lethal (Vogel & Nivard, 1993).

A single intraperitoneal dose of 125 mg thiourea/kg body weight administered to mice led to a weak increase in mutation rate (up to a factor of 3.6) in Salmonella strains TA 1530 and TA 1538 in a host-mediated assay, but negative results were obtained in Saccharomyces cerevisiae following a single intraperitoneal dose of 1000 mg/kg body weight. The examined tissue was the peritoneum (Simmon et al., 1979).

DNA repair

The effect of thiourea was investigated by means of the unscheduled DNA synthesis (UDS) test with primary rat hepatocyte cultures at concentrations ranging from 0.064 to 10 000 μg/litre as part of a collaborative study involving seven laboratories. None of the laboratories identified any induction of UDS. A further laboratory investigated the possible induction of DNA strand breaks by thiourea in primary rat hepatocytes using an alkaline elution technique. Thiourea also proved to have no positive effect in this study (Fautz et al., 1991).

A DNA repair test was carried out with Escherichia coli K-12343/113 at thiourea concentrations up to 329 mmol/litre (equivalent to 25 mg/ml; no further details on the concentration range were provided) in both the absence and presence of metabolic activation provided by the S9-mix from Aroclor 1254-induced rat liver. Thiourea had no effect with metabolic activation, but had a positive effect in its absence (Hellmér & Bolcsfoldi, 1992).

When primary cultures of isolated rat hepatocytes were treated with 5–25 mmol thiourea/litre, the induction of a relatively small linear increase in UDS was observed in the cells (Ziegler-Skylakakis et al., 1985). Very similar results had already been reported previously (Lonati-Galligani et al., 1983), although they were (presumably erroneously: see Rossberger & Andrae, 1987) interpreted as constituting a negative response.

Thiourea at concentrations of 30–300 mmol/litre induced single strand breaks in the DNA of primary cultures of isolated rat hepatocytes (Sina et al., 1983). The inhibitory effect of thiourea on the induction of DNA strand breakage due to various intercalating substances in mouse leukaemia cells might be the result of a change in chromatin structure. This could alter the activity of a topoisomerase responsible for the occurrence of strand breaks in cooperation with the intercalating substances (Pommier et al., 1983). The methods of detection of UDS were either autoradiography or liquid scintillation counting, and the DNA single strand breaks were detected with the alkaline elution assay.

Mitogenic effects

Thiourea has mitogenic properties. Older studies with high doses of thiourea (0.4 g, 1–14 times, intraperitoneal; unclear whether per animal or per kg body weight) produced a high mitosis rate in the liver without hepatocellular necrosis. Studies on partially hepatectomized rats showed similar results (MAK, 1988).

Reproductive toxicity

Effects on fertility

Thiourea can affect fertility as a result of hypothyroidism.

Thiourea was included in the diet of rats at concentrations of between 0.01 and 1% for 24 months, which were equivalent to doses ranging from 5 to 500 mg/kg body weight per day (see Table 4). A reduction or cessation of spermatogenesis and effects on the thyroid gland or other organs were observed at doses higher than 35 mg/kg body weight per day (Fitzhugh & Nelson, 1948).

Developmental toxicity

Thiourea had neither a maternally toxic nor a teratogenic effect when administered to rats on the 12th or 13th day of gestation as a single oral dose of 480 mg/kg body weight (Ruddick et al., 1976).

In a study in which 66 female sheep (18 growing lambs, 18 maiden ewes, 9 pregnant ewes; controls: 9 growing lambs, 9 maiden ewes, 3 pregnant ewes) were orally administered 0 or 50 mg thiourea/kg body weight daily for 2, 4, or 6 months (six treated and three controls per group), external genitalia were infantile and stunted in growing lambs, while they were pale anaemic and dry in maiden ewes. None of the growing lambs showed signs of estrus. Mammary development was retarded (Nasseri & Prasad, 1987b).

Thiourea (50 mg/kg body weight per day) was administered orally to four female lambs 6–8 months of age for 80 days (Alavi Shoushtari & Safaii, 1993). Size and weight of the reproductive tract (ovaries, uterine horn, and vagina) revealed a slight, although not statistically significant, decrease. Histological examination showed that follicles in the ovaries were atretic and that the endometrial cells were shorter than the controls, indicating that hypothyroidism probably suppresses the ovarian and other reproductive functions of female lambs.

[35S]Thiourea was shown to cross the placenta in mice and rats and to be preferentially stored in the thyroid gland, depending on the stage of development of this organ, where it affects iodine metabolism (Shepard, 1963). In a study in which groups of CF4 rats were treated with 0.2% thiourea in the drinking-water on days 1–14 of gestation, growth retardation and malformations of the nervous system and skeleton were present in treated offspring, although specific incidences of fetal effects were not given (Kern et al., 1980). Maternally toxic oral doses of 1000 mg thiourea/kg body weight administered to mice on the 10th day and to rats on the 12th or 14th days of gestation were likewise found to be embryotoxic. The rate of absorption of thiourea increased in live fetuses on the 18th and 20th days of gestation in mice and rats, respectively, without any evidence of malformations (Teramoto et al., 1981). Maturation defects were apparent on the 20th day of gestation in the fetuses of dams that had been treated with 0.25% thiourea in the drinking-water during the first 14 days (Kern et al., 1980). These effects can be attributed to the depressing action of thiourea on thyroid activity. It is thus not to be expected that such effects would occur at levels of thiourea that do not result in an inhibition of thyroid function.

In studies with pregnant ewes administered 50 mg thiourea/kg body weight daily for 2, 4, or 6 months, abortion, stillbirth, birth of weak/low-weight lambs, dystokia, and retention of placenta were common features. The severity of changes was dependent upon the stage of gestation when hypothyroidism was induced (Nasseri & Prasad, 1987b).

Eight male lambs aged 3–3.5 months were orally administered 50 mg thiourea/kg body weight daily for 3.5 months (Sokkar et al., 2000). There were four control lambs. The secondary iodine deficiency resulting from the administered thiourea caused hypothyroidism, which led to retardation of growth and interfered with the sexual maturity of the growing male lambs. The treated males did not show any sexual desire when introduced to ewes in estrus compared with control animals. Palpation of the testes of treated lambs revealed hydrocoele with small testes. The average weight of the testes of the hypothyroid lambs was significantly reduced (3.2 ± 0.255 g) compared with that of control lambs (8.9 ± 1.00 g). The testes showed ill developed, small, empty seminiferous tubules with thick basement membranes. The Sertoli cells were primitive and non-functional. The level of testosterone in the plasma of these hypothyroid lambs was not detectable.

Immunological, neurological, or other effects

Acute intoxication with thiourea has been linked with an increase in the level of histamine in the lungs and plasma (4.38 μg histamine/100 ml plasma was determined for rats administered thiourea intraperitoneally at 10 mg/kg body weight compared with 2.08 μg/100 ml in the controls) and with an increase in lung vessel permeability (Giri et al., 1991a). Rats developed tolerance to an otherwise lethal dose of thiourea (10 mg/kg body weight) when pretreated with a non-lethal dose (0.5 mg/kg body weight) over a period of 8 days. This tolerance was accompanied by a reduction in both lung vessel permeability and plasma histamine levels (Giri et al., 1991b).

Adult and sexually immature Sprague-Dawley rats were given Evans-Blue dye intravenously at 60 mg/kg body weight, followed by 10 or 100 mg thiourea/kg body weight, and sacrificed after 2 h. No difference was seen in lung permeability between control and 26-day-old treated animals. Increased permeability was seen in 50- and 65-day-old rats after treatment. The histamine content of the lung increased with age and after treatment with thiourea. The increased vascular permeability in response to thiourea in mature rats is associated with corresponding increases in lung and plasma histamine levels (Giri et al., 1991a).

[14C]Thiourea (0.6 mg/kg body weight) admin-istered intravenously to adult rats results in binding to lung protein (Hollinger & Giri, 1990).

The oedema-inducing effect of thiourea is probably due to the action of its oxidation product cyanamide and can be alleviated by treatment with hydroxyl radical scavengers such as dimethyl sulfoxide, ethanol, or mannitol (Fox et al., 1983). The adverse action of thiourea on the lungs of rats injected intraperitoneally with 0.3 mg/kg body weight could also be diminished by intraperitoneal treatment with the antiarrhythmic agents procainamide (at 4 mg/kg body weight), quinidine gluconate (20 mg/kg body weight), and lidocaine (30 mg/kg body weight) (Stelzner et al., 1987).

Treatment in vitro with 75 mmol thiourea/litre results in an inhibition of interleukin-8 production in human whole blood, the toxic effect of which can be suppressed by the administration of glutathione or cysteine (DeForge et al., 1992).

Mechanistic considerations

Administration of thiourea to healthy animals or humans leads to depression of thyroid function. It acts by inhibiting the peroxidase in the thyroid gland, resulting in decreased thyroid hormone production and increased proliferation due to an increase in the secretion of TSH (MAK, 1988; IARC, 2001). This could lead to tumour formation. This is a well recognized mechanism of action for non-genotoxic thyroid carcinogens (Capen et al., 1999). However, no definite conclusion regarding the mechanism of carcinogenicity can be made for thiourea, since it cannot totally be excluded that the possible genotoxicity of thiourea also plays a role.

It was shown in liver microsomes, in mammalian cells in culture (Ziegler, 1978; Poulsen et al., 1979; Ziegler-Skylakakis, 1998), and in intact rat liver (Krieter et al., 1984) that thiourea can form S-oxygenated products such as the reactive electrophiles formamidine sulfenic acid and formamidine sulfinic acid. The latter has been shown to be genotoxic in cultured mammalian cells (Ziegler-Skylakakis, 1998). The importance of the oxidative thiourea metabolites for the genotoxicity of thiourea needs further elucidation.

On the other hand, under the assumption that there is no direct interaction of thiourea with DNA, it was concluded that thyroid follicular neoplasia involves a non-linear dose–response process and would not develop unless there is prolonged interference with the thyroid–pituitary feedback mechanism (Hard, 1998).

There are several important species differences in thyroid gland physiology, which are important for the development of thyroid tumours. The half-life of T4 is much shorter in rats (12–24 h) than in humans (5–9 days), and the serum levels of TSH are 25 times higher in rodents than in humans. Further, rats require about a 10-fold higher production of T4 than do humans. In addition, the human plasma high-affinity T4-binding globulin is absent in rodents, cats, and rabbits. As a result, more free T4 is transported in the blood in these species, and therefore there are higher levels of metabolism and excretion of T4 in rodents, cats, and rabbits than in humans (Dohler et al., 1979; McClain, 1995; Dybing & Sanner, 1999). The weight of evidence suggests that rodents are more sensitive than humans to thyroid tumour induction due to hormonal imbalances that cause elevated TSH levels. Nevertheless, there are gaps in the available information (Hard, 1998; Capen et al., 1999).

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