Chronic progressive nephropathy in male F344 rats in 90-day toxicity studies: its occurrence and association with renal tubule tumors in subsequent 2-year bioassays

Abstract

The occurrence and severity of spontaneous chronic progressive nephropathy (CPN) in control male F344 rats as well as the frequency of treatment-related CPN exacerbation were histopathologically reevaluated. A series of 43 National Toxicology Program (NTP) 90-day toxicity studies comparing the influence of NIH-07 or NTP-2000 diets was examined. Relationships between the histopathologic findings at 90 days and renal tubule proliferative lesions recorded in subsequent 2-year bioassays for 24 chemicals were statistically analyzed. CPN lesions were observed in 100% of the control male rats regardless of diet, but CPN was more severe in control rats fed NIH-07. Approximately one-third of the 90-day studies demonstrated a treatment-related exacerbation of CPN severity, which was independent of diet. For chemicals that proceeded to 2-year bioassays, all studies with a statistically significant increase in renal tubule tumors (RTT) at 2 years had treatment-related exacerbation of CPN in the 90-day and 2-year studies. These findings indicate that CPN occurs ubiquitously in young male F344 rats and that treatment-related exacerbation of CPN in 90-day studies is a relatively common occurrence, having the potential to be predictive of an increased incidence of RTT in subsequent 2-year bioassays.

Figure 1.—

(a) A series of basophilic tubule profiles representing a single nephron affected by chronic progressive nephropathy (CPN), extending in a linear fashion (arrows) from the cortex, through the outer stripe of the outer medulla, and down to the inner stripe of the outer medulla junction. Diagnosis of CPN could be based on any of the profiles indicated by an arrow. However, this particular lesion with its discontinuous profiles would be scored as only one focus of CPN. (b) A series of hyaline (or colloid) casts in the inner stripe of the outer medulla represents the turns of a single tubule. Hyaline casts in the inner stripe of the outer medulla or inner medulla are characteristic of CPN and indicate more proximal (cortical) CPN involvement of the same nephron. The presence of an isolated cast of this type (arrows), without apparent association with a basophilic focus in the cortex, or linear basophilic tubules in the outer stripe of the outer medulla, would be counted as one CPN lesion.