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p-Nitrobenzoic Acid  2u Nephropathy in 13-week Studies is not Associated with Renal Carcinogenesis in 2-year Feed Studies
Kyha D. Williams
College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, 27606, USA
June Dunnick
Environmental Toxicology Program, National Institutes of Environmental Health Sciences, PO Box 12233, Research Triangle Park, North Carolina 27709, USA
John Horton
Environmental Toxicology Program, National Institutes of Environmental Health Sciences, PO Box 12233, Research Triangle Park, North Carolina 27709, USA
Arnold Greenwell
Environmental Toxicology Program, National Institutes of Environmental Health Sciences, PO Box 12233, Research Triangle Park, North Carolina 27709, USA
Sandra R. Eldridge
Pathology Associates International, 15 Woman's Mill Ct, Frederick, Maryland 21701, USA
Michael Elwell
Pfizer, Inc., Global Research and Development, MS 8274-31, Eastern Point Road, Groton, Connecticut 06340, USA
Robert C. Sills
Environmental Toxicology Program, National Institutes of Environmental Health Sciences, PO Box 12233, Research Triangle Park, North Carolina 27709, USA, sills{at}niehs.nih.gov
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, respectively. At 13 weeks, renal lesions included minimal to mild hyaline droplet accumulation in male rats and karyomegaly 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 morphologically similar to those described in  2u-globulin nephropathy. Using immunohistochemica l methods, 2u-globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistry was signifi cantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with 2u-globulin nephropathy 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 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 2u-globulin accumulation in male rats at 13 weeks, the minimal severity of nephropathy suggests that the degree of cytotoxicity was below the threshold, which would contribute to the development of renal tumors at 2 years.
Key Words: p-nitrobenzoic acid • hyaline droplets • 2u-globulin • nephropathy • cell proliferation • renal neoplasms • kidney.
Toxicologic Pathology, Vol. 29, No. 5,
507-513 (2001)
DOI: 10.1080/019262301317226302
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