Nesnow S, Mass M J, Ross J A, Galati A J, Lambert G R, Gennings C, Carter W H, Stoner G D
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Environ Health Perspect. 1998 Dec;106 Suppl 6(Suppl 6):1337-46. doi: 10.1289/ehp.98106s61337.
The binary, ternary, quaternary, and quintary interactions of a five-component mixture of carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) using response surface analyses are described. Initially, lung tumor dose-response curves in strain A/J mice for each of the individual PAHs benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), dibenz[a,h]anthracene (DBA), 5-methylchrysene (5MC), and cyclopenta[cd]pyrene (CPP) were obtained. From these data, doses were selected for the quintary mixture study based on toxicity, survival, range of response, and predicted tumor yields. The ratios of doses among PAHs were designed to simulate PAH ratios found in environmental air and combustion samples. Quintary mixtures of B[a]P, B[b]F, DBA, 5MC, and CPP were administered to male strain A/J mice in a 2(5) factorial 32-dose group dosing scheme (combinations of five PAHs each at either high or low doses) and lung adenomas were scored. Comparison of observed lung adenoma formation with that expected from additivity identified both greater than additive and less than additive interactions that were dose related i.e., greater than additive at lower doses and less than additive at higher doses. To identify specific interactions, a response surface analysis using response addition was applied to the tumor data. This response surface model contained five dose, ten binary, ten ternary, five quaternary, and one quintary parameter. This analysis produced statistically significant values of 16 parameters. The model and model parameters were evaluated by estimating the dose-response relationships for each of the five PAHs. The predicted dose-response curves for all five PAHs indicated a good estimation. The binary interaction functions were dominated for the most part by DBA and were inhibitory. The response surface model predicted, to a significant degree, the observed lung tumorigenic responses of the quintary mixtures. These data suggest that although interactions between PAHs do occur, they are limited in extent.
本文描述了利用响应面分析对致癌环境多环芳烃（PAHs）五组分混合物的二元、三元、四元和五元相互作用进行的研究。首先，获得了A/J品系小鼠对各单一PAHs（苯并[a]芘（B[a]P）、苯并[b]荧蒽（B[b]F）、二苯并[a,h]蒽（DBA）、5-甲基屈（5MC）和环戊[cd]芘（CPP））的肺肿瘤剂量-反应曲线。根据这些数据，基于毒性、存活率、反应范围和预测的肿瘤发生率，为五元混合物研究选择了剂量。PAHs之间的剂量比设计为模拟环境空气和燃烧样品中发现的PAH比例。将B[a]P、B[b]F、DBA、5MC和CPP的五元混合物以2(5)析因32剂量组给药方案（五种PAHs每种分别采用高剂量或低剂量的组合）给予雄性A/J品系小鼠，并对肺腺瘤进行评分。将观察到的肺腺瘤形成情况与根据加和性预期的情况进行比较，发现了与剂量相关的大于加和性和小于加和性的相互作用，即在较低剂量下大于加和性，在较高剂量下小于加和性。为了确定具体的相互作用，对肿瘤数据应用了使用响应加法的响应面分析。该响应面模型包含五个剂量、十个二元、十个三元、五个四元和一个五元参数。该分析产生了16个参数的统计学显著值。通过估计五种PAHs各自的剂量-反应关系来评估模型和模型参数。所有五种PAHs的预测剂量-反应曲线显示出良好的估计效果。二元相互作用函数在很大程度上由DBA主导，并且具有抑制作用。响应面模型在很大程度上预测了五元混合物观察到的肺致瘤反应。这些数据表明，虽然PAHs之间确实发生相互作用，但其程度有限。
