Standard and molecular NOAELs for rat testicular toxicity induced by flutamide.
An important step in the safety assessment of chemicals for humans is to determine the no observed adverse effect level (NOAEL) in toxicity studies conducted in animal models. With the increasing use of molecular tools in toxicity studies, a question often posed is how a NOAEL derived from molecular data compares to a NOAEL established using standard methods. The objective of the present study was to address this question when considering testicular toxicity. To do this, we assessed the effects of the reference antiandrogen flutamide on rat testes in a standard 28-day toxicity study using doses of 0.04-150 mg/kg/day. At necropsy, blood samples were collected for testosterone measurements. The testes were collected for histopathological assessment as well as for the evaluation of gene expression changes using quantitative PCR analyses. Results showed that increases in plasma testosterone level and Leydig cell hyperplasia were detected from 6 mg/kg/day. An alteration in the level of accumulation of a selection of genes was also detected from 6 mg/kg/day. This was the case for genes functionally associated with the testicular lesion, such as lipid metabolism and cell death/cell proliferation, as well as for genes not functionally associated with the lesion. Contrary to the misgivings, these data show that, using a standard 28-day toxicity study and a well-characterized adverse effect, the NOAEL based on transcript changes is similar to the NOAELs based on testosterone levels and histopathological examination.
Rouquié
David
D
Bayer CropScience, Department of, Research Toxicology, 06903 Sophia-Antipolis, France. david.rouquie@bayercropscience.com
Friry-Santini
Claire
C
Schorsch
Frédéric
F
Tinwell
Helen
H
Bars
Rémi
R
D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003627:Data Interpretation, Statistical; D005485:Flutamide / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006651:Histocytochemistry; D006965:Hyperplasia; D007985:Leydig Cells / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D018675:Toxicity Tests / Q000379:methods*; D043922:Toxicogenetics
D000726:Androgen Antagonists; D012333:RNA, Messenger; D013739:Testosterone; D005485:Flutamide