p-Nitrobenzoic Acid α2u Nephropathy in 13-week Studies is not Associated with Renal Carcinogenesis in 2-year Feed Studies

Abstract

The objective of this study was to characterize the renal toxicity and carcinogenicity of p-nitrobenzoi c acid in F344 rats. Dose levels in 13-week and 2-year studies ranged from 630-10,000 ppm and 1,250-5,000 ppm, respectivel y. At 13 weeks, renal lesions included minimal to mild hyaline droplet accumulation in male rats and karyomegal y in male and female rats. At 2 years, renal lesions included proximal tubule epithelial cell hyperplasia in male rats and oncocytic hyperplasia in high-dose male and female rats, and a decreased severity of nephropathy in males and females. The hyaline droplets in renal tubular epithelial cells of male rats at 13 weeks were morphologicall y similar to those described in a 2u -globulin nephropathy. Using immunohistochemica l methods, a 2u -globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistr y was signi cantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with a 2u -globulin nephropath y such as single-cell necrosis of the P2 segment epithelium or accumulation of granular casts in the outer medulla did not occur in the 13-week study. In addition, chronic treatment related nephrotoxic lesions attributed to accumulation of a 2u -globulin such as linear foci of mineralization within the renal papilla, hyperplasia of the renal pelvis urothelium and kidney tumors were not observed. Although there was histologic evidence of a 2u -globulin accumulation in male rats at 13 weeks, the minimal severity of nephropath y suggests that the degree of cytotoxicity was below the threshold, which would contribute to the development of renal tumors at 2 years.

Histiocytic Sarcoma in C57BL/6J Female Mice is Associated with Liver Hematopoiesis: Review of 41 Cases

“…However, as Ward et al (23), we do not retrieve such an association with HS, though the disease is often widespread in our 41 mice. In addition, the signification of the frequency of renal hyaline droplets in our control group remains elusive, as such droplets are otherwise mentioned only in nephrotoxicity studies (15,17,24).…”

Significance of the Renal Effects of Ethyl Benzene in Rodents for Assessing Human Carcinogenic Risk

“…Of greater biological significance, however, was the absence of granular casts at the OSOM/ISOM junction in the subchronic studies of both Stott et al (2001) and the NTP, and the absence of linear papillary mineralization in the NTP two-year study. These two facts suggest that the hyaline droplet-inducing property of ethyl benzene did not exceed the threshold of cytotoxicity needed for an association with renal tumor development through a mechanism of sustained cell loss and regeneration (Williams et al, 2001). However, it cannot be ruled out that this effect contributed as an additive factor superimposed on another, primary mode of action.…”

In Vivo Evaluation of the Oral Toxicity of the Chlorobutanol

“…A2u-globulin synthesis is age-dependent and reached a peak at 3 months old among male rats [32]. The function of this protein is not known, but it is filtered through the glomerulus and reabsorbed by the proximal tubule under normal conditions [33]. Generally, substances that cause an increased accumulation of a2u-globulin in the renal tubules are associated with increased renal tubule epithelial degeneration, necrosis, regeneration, and subsequent renal carcinogenicity [34,35].…”