Sequential study of the chronic nephrotoxicity induced by dietary administration of ethoxyquin in Fischer 344 rats

Groups of 3-week-old male and female Fischer 344 rats were administered 0.5% ethoxyquin-containing diet for varying periods of time, ranging from 4 weeks up to 18 months, to assess renal histopathology. The primary lesion observed was renal papillary necrosis in the male rat, commencing as interstitial degeneration of the papillary tip by 4 weeks exposure, and reaching a complete form of papillary necrosis by 24 weeks. The papillary necrosis in male rats was consistently accompanied by active pyelonephritis affecting the cortex, and urothelial hyperplasia in the renal pelvis. A marked sex difference was evident in that female rats developed papillary change at a later stage than males and the lesion never progressed beyond interstitial degeneration. A further sex difference associated with ethoxyquin treatment was the increasing cellular accumulation of lipofuscin-related pigment involving proximal tubules in female rats. Spontaneous chronic progressive nephropathy (CPN) was exacerbated by ethoxyquin in both males and females, but more so in the former. Proximal tubule hyperplasia was most frequently observed in ethoxyquin-treated males at the later sampling times. In all cases, such proliferative lesions were associated either with pyelonephritis or with the most advanced stages of CPN. Contrary to a previous report, there was no evidence that ethoxyquin directly induced preneoplastic renal tubule hyperplasia.