Mode of Action of Thyroid Tumor Formation in the Male Long–Evans Rat Administered High Doses of Alachlor

• Published in: Fundamental and applied toxicology 1996-09, Vol.33 (1), p.16-23
• Main Authors: Wilson, Alan G.E., Thake, Daryl C., Heydens, William E., Brewster, David W., Hotz, Kathy J.
• Format: Article
• Language: English
• Subjects: Acetamides - administration & dosage; Acetamides - toxicity; ACTIVIDAD ENZIMATICA; ACTIVITE ENZYMATIQUE; Administration, Oral; ALACHLORE; ALACLORO; Animals; Biological and medical sciences; Body Weight - drug effects; CARCINOGENESE; CARCINOGENESIS; Carcinogenicity Tests; EFECTOS SECUNDARIOS; EFFET SECONDAIRE; FOIE; GLANDULA TIROIDE; Glucuronosyltransferase - drug effects; Glucuronosyltransferase - metabolism; Herbicides - administration & dosage; Herbicides - toxicity; HIGADO; Homeostasis - drug effects; HORMONAS DE LA TIROIDE; HORMONE THYROIDIENNE; Hypothalamo-Hypophyseal System - physiopathology; Male; Medical sciences; METHODE D'APPLICATION; METODOS DE APLICACION; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; NEOPLASMAS; NEOPLASME; Organ Size - drug effects; PESO; Pesticides, fertilizers and other agrochemicals toxicology; POIDS; RAT; RATA; Rats; SERUM SANGUIN; SUERO SANGUINEO; Thyroid Gland - pathology; Thyroid Gland - physiopathology; Thyroid Hormones - blood; Thyroid Neoplasms - chemically induced; THYROIDE; THYROXINE; TIROXINA; TOXICIDAD; TOXICITE; Toxicology; TRANSFERASAS; TRANSFERASE; TRIIODOTHYRONINE; TRIYODOTIRONINA
• ISSN: 0272-0590; 1095-6832
• DOI: 10.1006/faat.1996.0138

Chronic administration of alachlor in the diet at a level of 126 mg/kg/day has previously been shown to cause an increase in benign thyroid follicular cell tumors in male Long–Evans rats. Studies were conducted to elucidate the mechanism of the alachlor-induced thyroid tumors in the male rat by evaluating changes in parameters that are collectively associated with a hormonally mediated mode of action for thyroid neoplasia. Male Long–Evans rats were administered 126 mg alachlor/kg body wt/day via the diet for up to 120 days. One group of animals was removed from alachlor-treated diet after 60 days and received untreated diet for an additional 60 days. Liver and thyroid weights and serum levels of triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH), as well as hepatic uridine diphosphate glucuronosyl transferase (UDPGT) activity, were determined at 7, 14, 28, 60, and 120 days of treatment. Liver and thyroid weights, hepatic UDPGT activity, and circulating levels of TSH were significantly increased in animals administered alachlor. These increases were seen as early as 7 days after alachlor administration. Circulating levels of T4in alachlor-treated animals were significantly decreased compared with controls at 7 days, but had returned to control levels by 60 days. T3levels were elevated at all time points except at 28 days. The changes in TSH and T3levels, hepatic UDPGT activity, and liver weights were all reversible on elimination of alachlor from the diet. Thyroid weights did not completely return to control levels after removal of alachlor from the diet, although some recovery was evident. The results of this study clearly suggest that alachlor-induced thyroid neoplasia, observed in previous chronic bioassays with alachlor, was associated with increases in circulating TSH levels. Increased metabolism of T4via hepatic enzymatic conjugation (i.e., T4-UDPGT) appeared to be responsible for the increased TSH levels. These effects were shown to be reversible on cessation of exposure to alachlor. In summary, evidence is presented for a hormonally mediated process for the development of thyroid follicular cell tumors.