ethylenethiourea and Adenoma

Five chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the same Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the five test compounds: methimazole from 2.5 to 10mM; nitrobenzene, potassium bromate, N,N'-diethylthiourea and ethylenethiourea from 1.25 to 5mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in potassium bromate-exposed thyroid cells from all the three donors and in those from two of three donors with either nitrobenzene or ethylenethiourea, but did not match the criteria for a positive response in thyroid cells from any of the donors with methimazole and N,N'-diethylthiourea. Consistently with their ability to induce thyroid tumors, all the five test compounds, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid. These findings suggest that the five test compounds might be carcinogenic to thyroid in humans.

Topics: Adenocarcinoma, Follicular; Adenoma; Animals; Bromates; Carcinogens; Cells, Cultured; DNA Damage; DNA Fragmentation; DNA Repair; Ethylenethiourea; Humans; In Vitro Techniques; Kidney; Liver; Male; Methimazole; Nitrobenzenes; Rats; Rats, Sprague-Dawley; Thiourea; Thyroid Gland; Thyroid Neoplasms

Groups of 50 male and 50 female Sprague-Dawley rats were fed diets containing 0, 75, 100, or 150 ppm ethylenethiourea (ETU) for 7 weeks, at which time subgroups of 10 animals from each group were killed. Subsequent subgroups of 10, 10, and 20 animals were killed after an additional 2, 3, and 4 weeks, respectively, on the control diet in order to examine whether the toxicological effects induced by ETU were reversible. In both sexes, the mean body weight and feed consumption were significantly decreased in all treated groups, while the mean thyroid weight (absolute as well as relative to both body and brain weight) appeared to increase linearly with dose. Mean T4 blood levels in animals fed 150 ppm ETU were significantly below those in controls. The magnitude of the changes in body weight, thyroid weight, and T4 blood levels observed during the first 7 weeks of the study decreased after ETU was removed from the diet. The statistical procedures developed and applied here may be useful in other experiments designed to assess the reversibility of other toxicological endpoints.

Topics: Adenoma; Animals; Body Weight; Carcinoma; Diet; Dose-Response Relationship, Drug; Ethylenethiourea; Female; Imidazoles; Male; Models, Biological; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred Strains; Thyroid Gland; Thyroid Neoplasms; Thyroxine; Triiodothyronine