Consideration of the mechanism of pulmonary adenogenesis in urethane-treated Swiss mice

Abstract

A number of investigators have observed a quadratic relationship between acute urethane dose and cumulative pulmonary adenoma incidence in mice. The hypothesis was tested that this dose-effect relationship may be explained by consideration of the elimination kinetics of urethane. Single doses of 0.4 to 1.8 mg urethane per g body weight were given ip to 6-week-old Swiss-Cox mice. The measure of internal exposure to the intact urethane molecule for a given external urethane dose was taken to be the area under the curve (AUC α) of a blood urethane concentration versus time plot. AUC α was linearly related to tumor prevalence. When urethane elimination was induced by pretreatment of the mice with p,p′-DDT, the linear relationship of AUC α to tumor prevalence was shifted. Reduction of tumor prevalence by p,p′-DDT pretreatment was more marked than that predicted on the basis of exposure to urethane. Thus, the kinetic evidence is consistent with biochemical evidence from other investigators supporting the premise that activation of urethane to a reactive metabolite is required for adenoma formation in the mouse lung. While exposure to the adenogenic moiety is evidently closely proportional to internal exposure to urethane in both pretreated and non-pretreated mice, p,p′-DDT pretreatment causes a shift in this proportionality.