The association between severe nephropathy and pheochromocytoma in the male F344 rat - The National Toxicology Program experience

The possible correlation between the severity of chronic progressive glomer ulonephropathy (CPN) and the incidence of adrenal pheochromocytoma was exam ined in selected studies of male Fischer 344 (F344) rats at the National To xicology Program (NTP). The NTP historical control database was first exami ned in order to determine whether there was association between the severit y of CPN and the occurrence of adrenal pheochromocytoma in unexposed animal s. Following this analysis, the 125 most recent NTP studies conducted in F3 44 rats were examined in order to determine how frequently chemicals that c ause increased severity of CPN show-ed an increased incidence of pheochromo cytoma. Finally, we examined the association between the incidence of pheoc hromocytoma and the severity of CPN in those NTP studies with chemically re lated increased rates of pheochromocytoma. In control male F344 rats surviv ing beyond 21 mo, the incidence of adrenal pheochromocytoma was consistentl y 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 s tudy controls. An association was not consistently observed when dosed grou ps were considered. Although 22% (28/125) of NTP studies reported a chemica lly related increased severity of CPN, only 3 of these reported a correspon ding significant increase in the incidence of pheochromocytoma. Of 6 NTP st udies that reported increased incidence of pheochromocytoma, animals with p heochromocytoma from 5 of those studies had some degree of increased severi ty of CPN. However, the estimated strength of the correlation with the seve rity of CPN varied from study to study and was often quite different from t hat indicated by an analysis of the more extensive NTP control databases. T he possible correlation between the severity of CPN and the incidence of ph eochromocytoma may influence interpretation of carcinogenic effects observe d at this site.