title: 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.
authors.affiliation: Private Consultant, 203 Paku Drive, Tairua 3508, New Zealand. gordonhard@msn.com
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Hard
authors.forename: Marcy I
authors.initials: MI
authors.lastname: Banton
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bretzlaff
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dekant
authors.forename: Jefferson R
authors.initials: JR
authors.lastname: Fowles
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Mallett
authors.forename: Douglas B
authors.initials: DB
authors.lastname: McGregor
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Roberts
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sielken
authors.forename: Ciriaco
authors.initials: C
authors.lastname: Valdez-Flores
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D018450:Disease Progression; D007674:Kidney Diseases / Q000503:physiopathology*; D051381:Rats