Eide I, Johnsen H G
Statoil Research Centre, Trondheim, Norway.
Environ Health Perspect. 1998 Dec;106 Suppl 6(Suppl 6):1373-6. doi: 10.1289/ehp.98106s61373.
Mixture design has been used to identify possible interactions between mutagens in a mixture. In this paper the use of mixture design in multidimensional isobolographic studies is introduced. Mutagenicity of individual nitro-polycyclic aromatic hydrocarbons (PAH) was evaluated is an organic extract of diesel exhaust particles (DEPs). The particles were extracted with dichloromethane (DCM). After replacing DCM with dimethyl sulfoxide, the extract was spiked with three individual nitro-PAH: 1-nitropyrene, 2-nitrofluorene, and 1,8-dinitropyrene. The nitro-PAH were added separately and in various combinations to the extract to determine the effects of each variable and to identify possible interactions between the individual nitro-PAH and between the nitro-PAH and the extract. The composition of the mixtures was determined by mixture design (linear axial normal) with four variables (the DEP extract and the three nitro-PAH, giving 8 different mixtures plus a triplicate centerpoint, i.e., a total of 11. The design supports a model with linear and interaction (product) terms. Two different approaches were used: traditional mixture design within a well-defined range on the linear part of the dose-response curves and an isobolographic mixture design with equipotent doses of each variable. The mixtures were tested for mutagenicity in the Ames assay using the TA98 strain of Salmonella typhimurium. The data were analyzed with projections to latent structures (PLS). The three individual nitro-PAH and the DEP extract acted additively in the Ames test. The use of mixture design either within a well-defined range of the linear part on the dose-response curve or with equipotent doses saves experiments and reduces the possibility of false interaction terms in situations with dose additivity or response additivity.
混合物设计已被用于识别混合物中诱变剂之间可能的相互作用。本文介绍了混合物设计在多维等效线图研究中的应用。评估了柴油尾气颗粒（DEP）有机提取物中单个硝基多环芳烃（PAH）的致突变性。颗粒用二氯甲烷（DCM）萃取。用二甲亚砜取代DCM后，提取物中加入三种单个硝基多环芳烃：1-硝基芘、2-硝基芴和1,8-二硝基芘。将硝基多环芳烃分别以各种组合添加到提取物中，以确定每个变量的影响，并识别单个硝基多环芳烃之间以及硝基多环芳烃与提取物之间可能的相互作用。混合物的组成通过具有四个变量（DEP提取物和三种硝基多环芳烃，产生8种不同混合物加一个重复中心点，即总共11种）的混合物设计（线性轴向正态）确定。该设计支持具有线性和相互作用（乘积）项的模型。使用了两种不同的方法：在剂量反应曲线线性部分的明确定义范围内进行传统混合物设计，以及对每个变量使用等效剂量的等效线图混合物设计。使用鼠伤寒沙门氏菌TA98菌株在Ames试验中测试混合物的致突变性。数据用潜在结构投影（PLS）进行分析。在Ames试验中，三种单个硝基多环芳烃和DEP提取物起相加作用。在剂量反应曲线线性部分的明确定义范围内或使用等效剂量进行混合物设计，可节省实验并减少在剂量相加或反应相加情况下出现错误相互作用项的可能性。
