Empirical Determination of Sufficiently Similiar Complex Mixtures

描述（申请人提供）：美国环保署（《对化学混合物进行健康风险评估的补充指南》，2000年）建议，当无法获得有关混合物的毒性数据时，可根据被认为在化学组成和成分比例方面“足够相似”的替代混合物的数据对混合物进行风险评估，如果可以获得，考虑到类似的生物处置和毒性。本研究的目的是开发方法来定义足够的相似性，在剂量反应性的许多化学品的混合物含有相同的成分，但其组成比例不同。该方法假设固定比例混合物的剂量反应数据是可用的。将应用统计等效性检验逻辑，根据研究者使用专家判断定义的特定生物学意义的不敏感区域，定义平均值、剂量-反应关系与观察到的混合物充分相似的混合物的边界比。一旦该方法如本文所述得到进一步发展，将进行模拟研究以阐明该方法的性质。模拟研究将基于至少三种化学品混合物的剂量-反应曲线数据，包括：（1）11种农药的混合物（2）根据对鱼类组织、母乳和其他人类接触来源的评价以及对甲状腺破坏的影响，以固定比例混合18种多卤代芳烃;（3）5种有机磷农药的混合物，其比例取决于从食物摄入的量和对神经毒性的影响。这项研究的结果将通过增加化学混合物风险评估的新方法来影响公共健康。特别是，不能对人类接触的所有可能的环境/工业相关化学混合物进行风险评估。受资助的项目将进一步开发/确定一种方法，以确定具有多种成分的混合物在剂量反应性方面的足够相似性。

DESCRIPTION (provided by applicant): The U.S. EPA (Suppl Guidance for Conducting Health Risk Assessment of Chemical Mixtures, 2000) suggests that when toxicity data are not available for a mixture of concern, the risk assessment of the mixture can be based on data for a surrogate mixture which is considered "sufficiently similar" in terms of chemical composition and component proportions, and when available, considerations of similar biological disposition and toxicity. The objective of this research is to develop methodology to define sufficient similarity in dose-responsiveness for mixtures of many chemicals containing the same components, but whose component ratios vary. The method assumes that dose-response data on a fixed-ratio mixture are available. Statistical equivalence testing logic will be applied to define boundary ratios for mixtures with mean, dose-response relationships sufficiently similar to an observed mixture, based on a specified biologically meaningful region of insensitivity as defined by the investigator using expert judgment. Once the methodology is further developed as described herein, simulation studies will be conducted to elucidate the properties of the approach. The simulation study will be based on data from at least three dose-response curves of mixtures of chemicals including: (1) a mixture of 11 pesticides (pyrethroids) and the effect on neurotoxicity; (2) a mixture of 18 polyhalogenated aromatic hydrocarbons in a fixed ratio based on evaluation offish tissue, breast rnilk and other sources of human exposure and the effect on thyroid disruption; (3) a mixture of 5 organophosphorous pesticides in a relevant ratio based on dietary exposures and the effect on neurotoxicity. The result of this research will impact public health by adding new approaches to the risk assessment of chemical mixtures. In particular, all possible environmentally/industrially relevant chemical mixtures to which humans are exposed cannot each be evaluated for risk. The funded project will further develop/characterize a method of determining sufficient similarity in dose-responsiveness for mixtures with many components.