Dose-response characteristics of uterine responses in rats exposed to estrogen agonists.

Abstract

Assays for uterine response have played major roles in developing an understanding of estrogen-mediated processes and for identifying compounds with hormonal activity. Data from assays measuring increases in uterine wet weight in rats were evaluated in terms of their dose-response characteristics. Analysis using a Hill equation found inconsistent estimates for the ED50 (concentration giving half-maximal response) and n (steepness of response) among the assays. This variability reflects disparate assay protocols and limitations of the dose-response data collected in the experiments. Although uterine wet weight is easily measured, it arises from several physiological processes (e.g., water retention, cell proliferation). This contributes to the assay variability with different protocols. The potential use of the Hill equation for dose-response analysis to estimate a benchmark dose was also considered using these data sets as surrogates for receptor-mediated toxicological effects. Strengths and weaknesses were identified, but overall the Hill equation should likely become a favored option for determining a benchmark dose, particularly when a data set demonstrates a maximal response. For screening purposes, empirical analysis using the Hill equation provides adequate information for classifying and prioritizing compounds. To develop an understanding of how incremental exposures to compounds with estrogen agonist activities would affect intact adult females, quantitative analyses are required that account for the pharmacokinetics of estradiol and subsequent interactions of the receptor complexes in regulating the responses.