Consideration of Rat Chronic Progressive Nephropathy in Regulatory Evaluations for Carcinogenicity

Abstract

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.

Transcriptomic alterations induced by Monuron in rat and human renal proximal tubule cells in vitro and comparison to rat renal-cortex in vivo

“…9,10 However, renal tubule cell toxicity was not been observed after exposure of male rats to MON for 3 days, which might have been expected is this was the mechanism of carcinogenesis. 32 We suggest from our findings that an up-regulation of cell cycle genes in association with the morphological changes observed in the nucleus after exposure may be contributing factors.…”

“…This possibility is considered as the tumour incidence in male rats is higher than that seen with chemicals that cause renal tumours via non-genotoxic mechanisms. 32 Metabolic activation to generate reactive metabolites has been suggested as a mechanism to produce cytotoxicity. 9,10 However, renal tubule cell toxicity was not been observed after exposure of male rats to MON for 3 days, which might have been expected is this was the mechanism of carcinogenesis.…”

War on Carcinogens: Industry Disputes Human Relevance of Chemicals Causing Cancer in Laboratory Animals Based on Unproven Hypotheses, Using Kidney Tumors as an Example

“…We were surprised at not being invited by Toxicological Sciences to counterpoint criticisms made by Hard et al, 33 since it is customary and standard practice among reputable scientific journals to offer authors of articles in their journal an opportunity to reply to criticisms of their work. Consequently and necessarily, we took it upon ourselves to prepare and submit a LTE to Toxicological Sciences to clarify misrepresentations by Hard et al 33 of our published evaluation on this topic. Surprisingly, the Editor-in-Chief of Toxicological Sciences rejected our LTE with no real explanation, only this statement:…”

“…Six months after our paper was accepted by Toxicological Sciences and published online, the same journal published online an extensive and directed criticism of our work by Hard and other industrial consultants. 33 That article, which was offered under the guise of a session summary at the Toxicology Forum's summer 2012 meeting, should have been published as a letter-to-the-editor (LTE) because it provided no new data on CPN and renal carcinogenicity, but focused almost exclusively on our work, which was only minimally discussed at that industrysponsored meeting. We were surprised at not being invited by Toxicological Sciences to counterpoint criticisms made by Hard et al, 33 since it is customary and standard practice among reputable scientific journals to offer authors of articles in their journal an opportunity to reply to criticisms of their work.…”

“…33 That article, which was offered under the guise of a session summary at the Toxicology Forum's summer 2012 meeting, should have been published as a letter-to-the-editor (LTE) because it provided no new data on CPN and renal carcinogenicity, but focused almost exclusively on our work, which was only minimally discussed at that industrysponsored meeting. We were surprised at not being invited by Toxicological Sciences to counterpoint criticisms made by Hard et al, 33 since it is customary and standard practice among reputable scientific journals to offer authors of articles in their journal an opportunity to reply to criticisms of their work. Consequently and necessarily, we took it upon ourselves to prepare and submit a LTE to Toxicological Sciences to clarify misrepresentations by Hard et al 33 of our published evaluation on this topic.…”