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Published on: March 29, 2019
Confounders for kidney carcinogenesis in rodent cancer bioassays
1Private Toxicology Consultant, 203 Paku Drive, Tairua 3508, New Zealand.
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.
Insights
Toxicologists must identify non-carcinogenic causes of kidney tumors in chemical safety tests. Recognizing false positives, like exacerbated chronic progressive nephropathy, is crucial for accurate carcinogenicity assessments.
Area of Science:
- Toxicology
- Carcinogenicity Testing
- Renal Pathology
Background:
- Long-term chemical safety testing requires accurate carcinogenicity assessment.
- Renal tubule tumors can arise from non-carcinogenic factors, complicating toxicological evaluations.
- Distinguishing true carcinogenic effects from other causes is essential for regulatory decisions.
Purpose of the Study:
- To highlight scenarios leading to false positive results in renal tubule tumor assessment during chemical carcinogenicity studies.
- To provide toxicologists with awareness of confounding factors in kidney tumor evaluation.
- To discuss specific examples of misleading findings in rodent carcinogenicity bioassays.
Main Methods:
- Review and discussion of known pathological and physiological phenomena in rodents.
- Analysis of specific situations that can mimic chemically induced renal tumors.
- Case examples illustrating potential misinterpretations in toxicological pathology.
Main Results:
- Exacerbation of chronic progressive nephropathy (CPN) in rats can lead to false positives.
- Atypical tubule hyperplasia, a precursor, can be confused with benign CPN-related proliferation.
- Spontaneous tumors (e.g., amphophilic-vacuolar tumors) and tubule dilatation may be misattributed.
- Chemically induced karyomegaly's predictive value for renal carcinogenicity is questionable.
Conclusions:
- Several non-carcinogenic conditions can be mistaken for chemically induced renal tumors in safety testing.
- Careful histopathological evaluation and understanding of rodent kidney diseases are vital.
- Accurate interpretation prevents erroneous conclusions regarding chemical carcinogenicity.
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