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

American Health Foundation, Valhalla, New York 10595

Philip H. Long

The Procter & Gamble Co., Miami Valley Laboratories, Cincinnati, Ohio 45239

James W. Crissman

The Dow Chemical Company, Midland, Michigan 48674

Jeffrey I. Everitt

Chemical Industries Institute of Toxicology, Research Triangle Park, North Carolina 27709

Barry L. Yano

The Dow Chemical Company, Midland, Michigan 48674

Timothy A. Bertram

The Procter & Gamble Co., Miami Valley Laboratories, Cincinnati, Ohio 45239

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.

Key Words: Kidney carcinogenesis • spontaneous neoplasia • Eker rat • genetic predisposition

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Toxicologic Pathology, Vol. 22, No. 5, 489-496 (1994)
DOI: 10.1177/019262339402200503


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Hard, G. C. Articles by Bertram, T. A. Search for Related Content PubMed PubMed Citation Articles by Hard, G. C. Articles by Bertram, T. A. Pubmed/NCBI databases Medline Plus Health Information Kidney Cancer Social Bookmarking                         What's this?