The pathogenesis of renal cortical tumours in rats fed 2% trisodium nitrilotriacetate monohydrate

To help assess the relationship between the renal toxicity and tumorigenicity associated with the administration of high doses of nitrilotriacetate (NTA) we have reviewed slides of sections from the kidneys of rats used in the National Cancer Institute bioassay of NTA. Trisodium NTA fed to Fischer 344 rats at 2% in the diet for 2 yr exerts a persistent toxic effect on the renal cortex which is manifested morphologically as vacuolation of proximal convoluted tubular epithelium and exacerbation of age-related nephrosis. Additionally, two pathogenic pathways leading to tumour formation in NTA-treated rats are suggested. A specific pathway initiated by vacuolation of proximal convoluted tubular epithelium leads to hyperplasia; reasons are advanced for the view that hyperplasia progresses to neoplasia. A possible concomitant pathway, which we suggest is nonspecific, is associated with regenerative proliferation in kidneys affected by severe age-related nephrosis. These data support the concept that there is a causal relationship between NTA-associated tubular toxicity and tumorigenicity. Doses of NTA that do not induce toxicity do not induce tubular tumours as demonstrated in this and in two other major long-term studies. Hence studies to investigate the pathogenesis of the toxic response provide an insight that suggests the basis for the development of NTA-associated tumours.