Confounders for kidney carcinogenesis in rodent cancer bioassays

Abstract

In the long-term safety testing of chemicals for carcinogenicity the toxicologist needs to be aware of a number of scenarios where renal tubule tumors, or their precursors, arise that are not due to a carcinogenic action of the test article. Situations producing false positive results in the kidney include exacerbation of chronic progressive nephropathy (CPN) in rats, confusion of atypical tubule hyperplasia (the obligate precursor of renal tubule tumor) with foci of benign CPN-related renal tubule cell proliferation, inclusion of spontaneous tumor entities, such as the amphophilic-vacuolar tumor, in the test article tumor count, the possibility of a link between spontaneous forms of tubule dilatation and renal tubule tumor formation in mice, and the supposed predictivity of chemically-induced karyomegaly for renal carcinogenicity in both rats and mice. Examples of these misleading situations are described and discussed.

Keywords: cystic tubules; forchlorfenuron; modes of action; mouse; renal tubule tumors.

Fig. 1.

Early stage of CPN is a very good example of simple tubule hyperplasia. The convolutions of a single tubule are basophilic and the lining retains a single cell structure. The tubule cells are smaller than normal, crowded together, and with thickened basement membrane. Toxicologic pathologists also call this lesion regeneration.

Fig. 2.

So-called “transitional cell hyperplasia” of the renal papilla. This lesion occurs in advanced to end-stage CPN, and consists of vesicular outpouchings of lining epithelium. It is called urothelial cell hyperplasia by some authorities, but the renal papilla lining is not urothelium and the lesion does not satisfy the criteria for hyperplasia. More appropriate terminology is “vesicular alteration of renal papilla lining”.

Fig. 3.

Atypical tubule hyperplasia, the obligate precursor of adenoma, consists of solid ingrowth of tubule cells into the tubule lumen. The lesion is encircled by a layer of flattened fibroblasts, indicating that it is expansile. The characteristic feature is particularly well shown in this example because of partial autolysis.

Fig. 4.

CPN-related tubule cell proliferation. This lesion, occurring in end-stage CPN, is confused with atypical tubule hyperplasia, but it is not an obligate precursor of neoplasms. Distinguishing features are: small poorly defined epithelial cells, and the prominent band of basement membrane surrounding the lesion.

Fig. 5.

A typical cross–section of the carcinoma in the high-dose males of the quercetin study. The tumor is characterized by well-defined lobules of amphophilic and vacuolated cells with central degeneration. It is unquestionably an A-V tumor which should be excluded from the test article-induced tumor count. (Courtesy of, and adapted from, Hard et al., 2007, Food Chem Toxicol 45, 600–608).

Fig. 6.

Renal tubule cell karyomegaly is an abnormally enlarged tubule cell nucleus. It is recommended that this diagnosis be reserved for nuclei of octaploidy or higher. (Courtesy of, and adapted from, Hard et al., 2000, Toxicol Sci 53: 237–244).