Atypical Tubule Hyperplasia and Renal Tubule Tumors in Conventional Rats on 90-Day Toxicity Studies

Bilateral, multicentric renal tubule tumors were found in 4 rats at the termination of 3 separate 90-day toxicity studies during the safety evaluation of 3 unrelated chemicals. The 3 studies were conducted at 2 separate locations, but the rats used were obtained from the same commercial source. The rat strains were Fischer-344 (1 male and 1 female case) and Sprague-Dawley (2 female cases). Three of the renal tumor cases were from either the high-dose or mid-dose treatment groups, and 1 case was an untreated control. The tumors were accompanied by multiple foci of atypical tubule hyperplasia but only in the tumor-bearing rats. There were no lesions associated with renal tumor pathogenesis in any of the remaining treated or untreated animals in the 3 studies. In addition, there was no indication of nephrotoxicity in the treated or untreated animals. Tumor morphology was characterized by a generally vacuolated appearance, eosinophilia, cytoplasmic and nuclear pleomorphism, and conspicuously hypertrophied nucleoli. The renal tubule tumors in these 90-day studies were compared to hereditary renal tubule tumors occurring in the Eker rat, a Long-Evans derivative with a genetic predisposition to this tumor type. The multiplicity of renal tubule tumors, early age of onset, and tumor morphology described in the cases from the 90-day studies were very similar to those characterizing the hereditary renal tumor model. The following evidence demonstrates that the 4 cases of renal tubule tumor developing in young rats in the course of 90-day studies were of spontaneous origin and not compound-induced: the tumors could not be reproduced by the test compound in a repetition of the 90-day toxicity study in which 2 of the cases occurred; pertinent renal lesions, including atypical hyperplasia, were seen only in tumor-bearing rats; there was an absence of nephrotoxicity in any of the treated rats and an absence of a dose-response relationship for the observed kidney alterations; 1 case was found in an untreated rat. The striking similarity of the tumors in these 4 cases to hereditary renal tumors occurring spontaneously in Eker rats suggests that the 90-day kidney alterations described here may be compatible with a genetic defect. As an alternative explanation, the possibility of a viral etiology was also considered.