邻苯二甲酸酯类雌激素活性联合作用模型分析

Model Assessing for the Combination Effects of Estrogenic Activity of Phthalates

环境雌激素对生命健康影响受到广泛关注,现行污染物环境标准制订和风险评价只针对单一化合物而非混合物效应,不足以保护生命安全与人类健康。为探讨环境雌激素的混合物效应,选择对雌激素敏感的人乳腺癌MCF-7细胞增殖实验,检测雌二醇(E2)、邻苯二甲酸酯类化合物(DBP和DEHP)的单一及其联合雌激素活性;基于单一化合物的浓度-反应曲线,运用浓度相加(CA)和独立作用(IA)模型对混合物的毒性进行预测,并将模型预测结果与混合物实验数据进行比较分析。结果表明,E2、DBP、DEHP对MCF-7细胞的单一作用数据可通过Weibull方程拟合,由拟合方程得到的半数效应浓度(EC50)及95%置信区间分别为3.450×10-6(2.373×10-6~1.675×10-5)、5.138(1.489~1.082×10)、1.186(4.478×10-1~2.24)μmol·L-1;3种化合物的混合物数据亦可通过Weibull、Logistic和Exp Gro1方程进行有效拟合,混合物效应与化合物单独作用产生的效应具有显著性差异;3种化合物表现非相似联合作用,利用独立作用(IA)模型预测混合物效应较为可靠,外源性环境雌激素与内源性雌激素联合作用产生的混合效应显著。环境雌激素混合物毒性可以通过相加作用模型预测,为环境复合污染的风险评价和管理提供基础数据。

Estrogens in the environment have received extensive concerns due to their potential risks to human health. The present environmental standards and risk assessment procedures have limitation in the protection of human health and safety, because they are on the basis of the single effects of chemical compounds, rather than the combined effects. To investigate the combined effects of estrogens, the single and joint toxicities of three estrogens, including estradiol （E2） and phthalic acid ester compounds （DBP and DEHP）, were investigated using the estrogen-sensitive MCF-7 human breast cancer cells proliferation assay. The individual concentration-response curves of the three estrogens were applied to predict the joint toxicity of their mixtures according to the concentration addition （CA） and the independent action （IA） models. The predicted concentration-response curves were further compared with the experimental data. The results showed that the single effects of E2, DBP, and DEHP were well fitted by Weibull equation, and their EC50 （95% confidence interval） values were 3.450×10^-6 （2.373×10^-6-1.675×10^-5） μmol ·L^-1, 5.138 （1.489-10.820） μmol ·L^-1, and 1.186 （0.448-2.240） μmol ·L^-1, respectively. The effect from the mixtures of the three estrogens were well described by Weibull, Logistic, and ExpGro1 equations, while significant differences were observed between the single effects of the three estrogens and the combined effects of their mixtures. The three compounds showed dissimilar joint actions, and the IA model was more appropriate to predict the combined effects compared to the CA model. The combined effects of exogenous environmental estrogen and endogenous estrogen were significant. Overall, the toxicity of estrogens mixtures can be predicted by the additive model, providing the basic data for the risk assessment and management of combined pollution in the environment.