P-Nitrobenzoic acid alpha2u nephropathy in 13-week studies is not associated with renal carcinogenesis in 2-year feed studies.

The objective of this study was to characterize the renal toxicity and carcinogenicity of p-nitrobenzoic 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 hvaline droplets in renal tubular epithelial cells of male rats at 13 weeks were morphologically similar to those described in alpha2u-globulin nephropathy. Using immunohistochemical methods, alpha2u-globulin accumulation was associated with the hyaline droplets. In addition, at 13 weeks, cell proliferation as detected by PCNA immunohistochemistry was significantly increased in males exposed to 5,000 and 10,000 ppm when compared to controls. Cytotoxicity associated with alpha2U-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 alpha2u-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 alpha2u-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.

Evaluation of distraction osteogenesis by scanning electron microscopy.

A model of bifocal distraction osteogenesis in the canine model was used to assess and quantitate the mineral content of the newly forming bone within the canine mandible. A 2-cm defect was created in the body of the mandible, and after a posterior osteotomy, the transport disk was advanced at 0.25 mm per 8 hours for 21 days and then held in rigid fixation for an additional week. As a control for this study, three additional dogs underwent the same procedure with the exception that the transport disk was not advanced. Electron dispersive spectroscopy analysis was performed on the newly formed regenerate bone and compared with areas of existing cortical bone of both the transport disk and the mandible. In the control model, special note was made of the pericortical callus at the osteotomy site as well as of the regenerative bone that filled the 2-cm defect in the body of the mandible. Calcium/phosphorous ratios were used to assess the composition of the mineralized regions of the mandible. The regenerate bone that filled the defect and the mineralized callus surrounding the site of osteoclasis in the control mandible were significantly different in composition when compared with the regenerate bone that formed during distraction osteogenesis. This suggests that distraction osteogenesis may effect an initial matrix production that is more similar in composition to the mature cortical bone from which it was derived than does periosteal regeneration and filling of an osseous defect.