Dose-response relationships in chemical carcinogenesis: renal mesenchymal tumours induced in the rat by single dose dimethylnitrosamine.

A single intraperitoneal dose of dimethylnitrosamine (DMN) given to weanling rats after 3 days' treatment with a protein-free diet results in the induction of renal mesenchymal tumours, the incidence of which is related to the dose of DMN in a sigmoid dose-response curve. The number of tumours per kidney is small, most animals given 40 mg/kg DMN (the TD100) having either one or two tumours in each kidney. However, within a few days of dosing a large number of small proliferative foci of mesenchymal cells, which resemble the tumours, appears in the renal cortex. The number of these foci is linearly related to the dose of DMN. By 12 weeks, the majority of these foci have disappeared, leaving an essentially normal kidney with only one or two developing tumours. The initial amount of methylation of guanine at the O6 and 7 positions in the kidney DNA measured 18 h after dosing is also linearly related to the dose of DMN. Thus, the formation of the early lesions is directly proportional to the amount of DNA alkylation, but the eventual tumour incidence is not. It is suggested that the mechanisms which operate to remove the majority of the early proliferative foci determine the shape of the dose-response curve for the tumours, which is independent of the initial alkylation levels.