Gennings Chris, Carter W Hans, Casey Michelle, Moser Virginia, Carchman Richard, Simmons Jane Ellen
Solveritas, L.L.C., Richmond, VA 23219, USA.
Environ Toxicol Pharmacol. 2004 Nov;18(2):115-25. doi: 10.1016/j.etap.2004.03.012.
The protection of human health from the adverse effects of cumulative environmental exposure to chemical mixtures is an important issue. Of particular interest is the detection and characterization of interaction among chemicals in complex mixtures. Response surface methodology, often supported by factorial designs, is the classical statistical experimental approach. Fixed-ratio ray designs, which may include the use of single chemical data in addition to data along mixture ray(s), have been proposed as an alternative approach. Such designs permit a reduction in the amount of experimental effort when the region of interest can be restricted to exposure-relevant mixing ratios. A 'single chemicals required' (SCR) approach and a 'single chemicals not required' (SCNR) approach are both described. The methods are illustrated with a five-chemical mixture of organophosphorus pesticides-acephate (ACE), diazinon (DIA), chlorpyrifos (CPF), malathion (MAL) and dimethoate (DIM). Their relative proportions in the mixture were based on the relative dietary human exposure estimates of each chemical as projected by the U.S. EPA Dietary Exposure Evaluation Model (DEEM). Use of the SCR and SCNR methods for binary endpoints are demonstrated using a dichotomized gait score as an indication of toxicity. For both methods, the overall hypothesis of additivity was rejected, indicating significant departure from additivity when the five pesticides were combined at the specified mixing ratio. By comparison of the predicted response under additivity to the modeled response of the experimental mixture data this departure from additivity was characterized as synergy (greater than additive toxicity). To examine the influence of malathion in the mixture, it was removed from the five-pesticide mixture (full ray) and the remaining four chemicals (reduced ray) were combined at the same relative proportions used in the full fixed-ratio ray There was not a significant departure from additivity along the ray with the four remaining pesticides omitting malathion. Thus, although malathion was not dose-responsive alone, it significantly interacted with the other pesticides.
保护人类健康免受化学混合物累积环境暴露的不利影响是一个重要问题。特别令人感兴趣的是复杂混合物中化学物质之间相互作用的检测和表征。响应面方法通常由析因设计支持，是经典的统计实验方法。固定比例射线设计，除了沿混合物射线的数据外，可能还包括使用单一化学物质的数据，已被提议作为一种替代方法。当感兴趣的区域可以限制在与暴露相关的混合比例时，这种设计可以减少实验工作量。本文描述了“需要单一化学物质”（SCR）方法和“不需要单一化学物质”（SCNR）方法。用有机磷农药乙酰甲胺磷（ACE）、二嗪农（DIA）、毒死蜱（CPF）、马拉硫磷（MAL）和乐果（DIM）的五化学物质混合物对这些方法进行了说明。它们在混合物中的相对比例基于美国环境保护局膳食暴露评估模型（DEEM）预测的每种化学物质的相对膳食人体暴露估计值。使用二分步态评分作为毒性指标，展示了SCR和SCNR方法用于二元终点的情况。对于这两种方法，加性的总体假设都被拒绝，表明当这五种农药以指定的混合比例组合时，显著偏离加性。通过将加性下的预测响应与实验混合物数据的建模响应进行比较，这种偏离加性被表征为协同作用（大于加性毒性）。为了研究马拉硫磷在混合物中的影响，将其从五农药混合物（全射线）中去除，其余四种化学物质（简化射线）以与全固定比例射线相同的相对比例组合。在省略马拉硫磷的其余四种农药的射线上，没有显著偏离加性。因此，尽管马拉硫磷单独时对剂量无反应，但它与其他农药有显著相互作用。
