Journal Article

Consideration of Rat Chronic Progressive Nephropathy in Regulatory Evaluations for Carcinogenicity

Gordon C. Hard, Marcy I. Banton, Robert S. Bretzlaff, Wolfgang Dekant, Jefferson R. Fowles, Anthony K. Mallett, Douglas B. McGregor, Kathleen M. Roberts, Robert L. Sielken, Ciriaco Valdez-Flores and Samuel M. Cohen

in Toxicological Sciences

Volume 132, issue 2, pages 268-275
Published in print April 2013 | ISSN: 1096-6080
Published online October 2012 | e-ISSN: 1096-0929 | DOI:

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Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical.

Keywords: atypical tubule hyperplasia; chronic progressive nephropathy; end-stage renal disease; renal tubule tumor; mode of action; human relevance.

Journal Article.  6339 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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