Dose‐Response Carcinogenicity in Rats on Low‐dose Levels of N‐Ethyl‐N‐nitrosourethane

Abstract

A dose‐response study on the carcinogenicity of N‐ethyl‐N‐nitrosourethane (ENUR) was undertaken to examine its effect at low doses. Six‐week‐old female F344 rats were divided into 5 groups, each consisting of 40 animals. ENUR was dissolved in distilled water at dose levels of 0 (control), 0.15, 0.6, 2.5 and 10 ppm, and rats were given these solutions ad libitum for 2 years. Significant increase of the total tumor incidences and shortening of the mean survival times were observed in groups given 2.5 and 10 ppm ENUR. In groups given 0.6 ppm or more ENUR, digestive tract tumors were induced dose‐dependently. They were restricted to the upper digestive tract from the oral cavity to the forestomach, and were histologically squamous cell papillomas or carcinomas. Dose‐related differences in the location and incidence of these tumors were found. The virtually safe doses (VSDs) calculated by using the Weibull, Logit and Probit models were 0.365 × 10‐2, 0.110 × 10‐1 and 0.779 × 10‐1 ppm, respectively. The VSDs estimated in the present study are discussed in comparison with those of other carcinogens.

Induction of Squamous Cell Carcinomas in the Salivary Glands of Rats by Potassium Iodide

“…However, in the historical data for untreated control F344 rats from carcinogenicity studies performed in our laboratory [2][3][4][5][6][7][8][9] and in the literature historical data on control F344 rats [10][11][12] used for carcinogenicity studies, no spontaneous occurrences of SCCs in the salivary gland are recorded. Therefore, the incidence of SCCs in the 1000 ppm group in the present study can not be ignored, and the possibility must be entertained that the SCCs are related to the treatment with large amounts of KI.…”

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

“…Studies designed to evaluate a threshold effect showed that at low doses the effects did not differ from the control values and have been used to calculate a 'virtual safe dose', a 'practical threshold' or a 'no-adverse-effect-level' (NOAEL). 9,10 Although such information adds to the assumption of a no effect level at low doses, they are challenged by the argument that the statistical power is insufficient to differentiate between the low dose effects and the controls. Even in a study using 40 800 trout in a ED 001 tumour bioassay, 11 it was concluded that the use of over 30 000 animals did not provide proof that a threshold was reached.…”

Thresholds for DNA-Reactive (Genotoxic) Organic Carcinogens

“…Indeed, a number of studies document NOAELs for the carcinogenicity of such agents [14][15][16][17][18][19][20][21] . Using a mechanistic approach to address the question of thresholds, we 79,80 have provided further evidence of NOAELs for DNA-reactive carcinogens in rat liver carcinogenesis.…”

“…In fact, most carcinogenicity studies that use low doses of DNA-reactive carcinogens have been interpreted as showing no threshold [10][11][12][13] . Nevertheless, several investigators have reported no-adverse-effect-levels (NOAELs) for preneoplastic or neoplastic lesions in experimental models with DNA-reactive carcinogens [14][15][16][17][18][19][20][21] . In this review, the reasoning and evidence supporting the existence of NOAELs or thresholds for DNA-reactive carcinogens in experimental models is set forth.…”