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Development and application of an integrated addition and interaction model of mixture toxicity.

機(jī)譯：混合毒性綜合添加和相互作用模型的開發(fā)和應(yīng)用。

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The focus of this work was to elucidate general principles of chemical interactions among mixture constituents using mathematical modeling approaches. Mixtures of diverse acting chemicals displaying both toxicokinetic and toxicodynamic interactions were assessed. Endpoints measured in these assessments ranged from acute toxicity to molecular adaptive responses in Daphnia magna . An Integrated Addition and Interaction (IAI) model of mixture toxicity was constructed and validated using mixtures of organophosphate pesticides (malathion and parathion), chlorophenols (2-chlorophenol and 4-chlorophenol), and the P450 inhibitor piperonyl butoxide. Modeled data was compared to experimentally derived data from Daphnia magna acute toxicity assays. Toxicokinetic interactions between the organophosphates and piperonyl butoxide were characterized and incorporated into the model to accurately predict mixture toxicity. Unexpected toxicodynamic interactions between organophosphates and chlorophenols were assessed.; Next, we developed a molecular endpoint for use in mixture modeling. We explored endocrine-mediated stress signaling in daphnids towards this end. We determined that juvenoid hormones induce hemoglobin mRNA and protein production. Hemoglobin expression in daphnids provided a promising molecular endpoint for use in mixture toxicity assessments. We identified the cis-acting juvenoid response element (JRE) that is likely responsible for activating the hemoglobin gene in response to juvenoids. The JRE was used to capture a specific protein that may prove to be the juvenoid receptor. Hemoglobin 2 (hb2) was identified as a highly inducible molecular endpoint which responds to multiple signaling pathways.; The hb2 gene was used to model molecular interactions of chemical mixtures. We demonstrated that the ubiquitous herbicide atrazine induced hb2 expression, while having no obvious relatedness to juvenoid hormones. Additive effects of binary mixtures of atrazine and the juvenoid pyriproxyfen were modeled and experimentally assessed to determine whether atrazine induced the hb2 gene via the juvenoid signaling pathway. Results indicated that atrazine was not inducing hb2 through this endocrine pathway.; In summary, mathematical models of mixture toxicity can be used to predict the joint effects of diverse chemicals displaying interactions, identify unexpected interactions, and elucidate potential mechanisms of interaction.
機(jī)譯：這項(xiàng)工作的重點(diǎn)是使用數(shù)學(xué)建模方法闡明混合物成分之間化學(xué)相互作用的一般原理。評估了表現(xiàn)出毒代動(dòng)力學(xué)和毒動(dòng)力動(dòng)力學(xué)相互作用的多種不同作用化學(xué)品的混合物。在這些評估中所測的終點(diǎn)從急性毒到大蚤的分子適應(yīng)性反應(yīng)。使用有機(jī)磷酸酯農(nóng)藥（馬拉硫磷和對硫磷），氯酚（2-氯酚和4-氯酚）和P450抑制劑胡椒基丁醚的混合物構(gòu)建并驗(yàn)證了混合物毒性的綜合加成和相互作用（IAI）模型。將建模數(shù)據(jù)與來自大型蚤（Daphnia magna）急性毒性試驗(yàn)的實(shí)驗(yàn)數(shù)據(jù)進(jìn)行比較。表征了有機(jī)磷酸酯和胡椒基丁醚之間的毒代動(dòng)力學(xué)相互作用，并將其納入模型以準(zhǔn)確預(yù)測混合物毒性。評估了有機(jī)磷酸酯和氯酚之間意外的毒動(dòng)力相互作用。接下來，我們開發(fā)了用于混合物建模的分子終點(diǎn)。為此，我們探索了水蚤中內(nèi)分泌介導(dǎo)的應(yīng)激信號(hào)傳導(dǎo)。我們確定了類黃酮激素可誘導(dǎo)血紅蛋白mRNA和蛋白質(zhì)產(chǎn)生。蚤類中的血紅蛋白表達(dá)為混合物毒性評估提供了有希望的分子終點(diǎn)。我們確定了順式作用的幼體反應(yīng)元件（JRE），它可能負(fù)責(zé)激活響應(yīng)于幼體的血紅蛋白基因。 JRE用于捕獲可能被證明是類幼體受體的特定蛋白質(zhì)。血紅蛋白2（hb2）被確定為高度可誘導(dǎo)的分子終點(diǎn)，可響應(yīng)多種信號(hào)通路。 hb2基因用于模擬化學(xué)混合物的分子相互作用。我們證明無處不在的除草劑at去津誘導(dǎo)hb2表達(dá)，而與少年激素沒有明顯的相關(guān)性。建模和實(shí)驗(yàn)評估阿特拉津和少年似的吡咯烷酚的二元混合物的加和效應(yīng)，以確定阿特拉津是否通過少年類信號(hào)通路誘導(dǎo)hb2基因。結(jié)果表明阿特拉津不通過該內(nèi)分泌途徑誘導(dǎo)hb2?？傊?，混合物毒性的數(shù)學(xué)模型可用于預(yù)測顯示相互作用的多種化學(xué)物質(zhì)的聯(lián)合作用，識(shí)別意外相互作用，并闡明潛在的相互作用機(jī)理。

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