The Association Between Severe Nephropathy and Pheochromocytoma in the Male F344 Rat— The National Toxicology Program Experience

Abstract

The possible correlation between the severity of chronic progressive glomerulonephropathy (CPN) and the incidence of adrenal pheochromocytoma was examined in selected studies of male Fischer 344 (F344) rats at the National Toxicology Program (NTP). The NTP historical control database was first examined in order to determine whether there was association between the severity of CPN and the occurrence of adrenal pheochromocytoma in unexposed animals. Following this analysis, the 125 most recent NTP studies conducted in F344 rats were examined in order to determine how frequently chemicals that cause increased severity of CPN showed an increased incidence of pheochromocytoma. Finally, we examined the association between the incidence of pheochromocytoma and the severity of CPN in those NTP studies with chemically related increased rates of pheochromocytoma. In control male F344 rats surviving beyond 21 mo, the incidence of adrenal pheochromocytoma was consistently higher in animals with more severe CPN. This association was significant ( p < 0.05) both for 900 NTP inhalation study controls and 900 NTP feeding study controls. An association was not consistently observed when dosed groups were considered. Although 22% (28/125) of NTP studies reported a chemically related increased severity of CPN, only 3 of these reported a corresponding significant increase in the incidence of pheochromocytoma. Of 6 NTP studies that reported increased incidence of pheochromocytoma, animals with pheochromocytoma from 5 of those studies had some degree of increased severity of CPN. However, the estimated strength of the correlation with the severity of CPN varied from study to study and was often quite different from that indicated by an analysis of the more extensive NTP control databases. The possible correlation between the severity of CPN and the incidence of pheochromocytoma may influence interpretation of carcinogenic effects observed at this site.

Comparison of Past and Recent Historical Control Data in Relation to Spontaneous Tumors During Carcinogenicity Testing in Fischer 344 Rats

“…food intake), body weight [16][17][18][19][20][21] , housing 22,23 and certain kinds of morbidity such as CPN 24 . In regard to the studies included in the present survey, there were no differences in diet composition or housing conditions.…”

“…Various factors, including diet [5][6][7][8][9][10][11][12][13][14][15] , body weight [16][17][18][19][20][21] , housing 22,23 and certain kinds of morbidity such as chronic progressive nephropathy (CPN) 24 , influence the occurrence of tumors. Nyska et al 24 suggested that there may be a positive correlation between the severity of CPN and the incidence of pheochromocytomas in Fischer 344 rats.…”

“…Nyska et al 24 suggested that there may be a positive correlation between the severity of CPN and the incidence of pheochromocytomas in Fischer 344 rats. In addition, a number of investigators have reported an association between tumor incidence and body weight in rodents [16][17][18][19][20][21] .…”

“…CPN, a common age-related lesion in male rats, is known to exert secondary effects on tumorigenesis. Nyska et al 24 suggested the possibility that the severity of CPN is positively correlated with the rate of production of pheochromocytoma in male Fischer 344 rats, although this is somewhat controversial among researchers. In animals with severe CPN, calcium/phosphorous homeostasis is severely disturbed.…”

Effect of Diet and Animal Care/Housing Protocols on Body Weight, Survival, Tumor Incidences, and Nephropathy Severity of F344 Rats in Chronic Studies

“…Nyska et al (21) suggested that increased severity of nephropathy may be associated with disturbed calcium and phosphorous homeostasis, secondary hyperparathyroidism leading to hypercalcemia (3). Perturbation in calcium homeostasis was documented to be associated with increased chromaffin cell proliferation and pheochromocytoma (13,39,40).…”