Feasibility and potential gains of enhancing the subacute rat study protocol (OECD test guideline no. 407) by additional parameters selected to determine endocrine modulation. A pre-validation study to determine endocrine-mediated effects of the antiandrogenic drug flutamide

Groups of five male and five female Wistar rats were treated by gavage with 0, 1, 10, and 100 mg flutamide/kg body weight for at least 28 days to investigate whether proposed enhancements to the current subacute rodent OECD test guideline no. 407 could be included into the testing routine, which of...

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Veröffentlicht in:Archives of toxicology 2001-04, Vol.75 (2), p.65-73
Hauptverfasser: ANDREWS, P, FREYBERGER, A, HARTMANN, E, EIBEN, R, LOOF, I, SCHMIDT, U, TEMEROWSKI, M, BECKA, M
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Sprache:eng
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Zusammenfassung:Groups of five male and five female Wistar rats were treated by gavage with 0, 1, 10, and 100 mg flutamide/kg body weight for at least 28 days to investigate whether proposed enhancements to the current subacute rodent OECD test guideline no. 407 could be included into the testing routine, which of the current and/or additional parameters would detect endocrine-mediated effects of flutamide reliably and sensitively, and to provide information on intra-laboratory variability. Two identical studies were performed concurrently. The enhanced protocol requests the additional determination of the specific hormones triiodothyronine, thyroxine, thyroid stimulating hormone, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin, testosterone, corticosterone; of oestrus cyclicity and necropsy of all females in the dioestrus stage; of the number of homogenization-resistant testicular spermatids and the number, motility, viability, and morphology of cauda epididymal spermatozoa; of additional organ weights (pituitary, ovaries, uterus, thyroid, male accessory reproductive organs); and of the histopathology of additional organs (pituitary, epididymides, coagulation glands, pancreas, vagina). From a technical standpoint, it was possible to conduct a study according to the enhanced protocol, however, with substantial additional effort, an increase in costs by some 67%, and logistic problems. In line with the specific pharmacological effect of flutamide, treatment-related changes were mainly found in male rats, while females were hardly affected by 100 mg/kg. In male rats, 100 mg/kg was the maximal tolerated dose resulting in reduced body weight gain, but no or little other effects on clinical, haematological, clinico-chemical, or behavioral parameters, and 1 mg/kg was the no-observed-adverse-effect level. Antagonism of peripheral androgen receptors by flutamide resulted in decreased relative organ weights of male accessory reproductive organs, changes that were reliably detected in both studies at 100 mg/kg, but only in one of both studies at 10 mg/kg. Corresponding histopathological changes were also detected reliably at 100 mg/kg. Antagonism of central androgen receptors by flutamide increased LH and FSH levels. LH stimulation of testicular Leydig cells in turn increased testosterone and estradiol levels. Again, all these changes were detected reliably at 100 mg/kg, but only in one of both studies at 10 mg/kg. Corresponding histopathological
ISSN:0340-5761
1432-0738
DOI:10.1007/s002040100214