Meek M E Bette, Bucher John R, Cohen Samuel M, Dellarco Vicki, Hill Richard N, Lehman-McKeeman Lois D, Longfellow David G, Pastoor Timothy, Seed Jennifer, Patton Dorothy E
Health Canada, Ottawa, Ontario, Canada.
Crit Rev Toxicol. 2003;33(6):591-653. doi: 10.1080/713608373.
The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.
人类相关性框架（HRF）概述了一个四部分的过程，该过程始于实验室动物的作用模式（MOA）数据，用于评估动物肿瘤与人类的相关性。借鉴美国环境保护局（EPA）和国际化学品安全规划署（IPCS）关于动物MOA分析的提议，HRF扩展了这些分析，以包括对假定的动物MOA与来自人类数据源的相关信息之间的可比性或缺乏可比性进行系统评估。HRF是通过一系列代表几种不同MOA的案例研究发展而来的。根据动物和人类来源提供的数据，HRF分析产生了不同的结果，一些导致了完整的风险评估，而另一些则终止了该过程。有两个案例需要进行完整的风险评估。一个是默认情况：当数据不足以自信地假定试验动物的MOA时，假定动物肿瘤数据与风险评估相关，因此需要进行完整的风险评估。另一个是基于数据的发现结果，即动物MOA与人类相关。对于本文研究的特定MOA和终点组合，对于涉及动物和人类细胞毒性和细胞增殖的潜在相关MOA（案例研究6，氯仿）以及尿路结石的形成（案例研究7，三聚氰胺），需要进行全面的风险评估。在其他情况下，当对所研究的化学物质和终点组合进行基于数据的发现表明与肿瘤相关的动物MOA不太可能在人类中出现时，就没有什么理由继续对该组合进行风险评估。同样，当定性考虑确定了特定于试验物种的MOA，或者定量考虑表明动物MOA不太可能在人类中发生时，此类危害发现通常具有决定性，对于正在研究的终点-MOA组合，无需进一步进行风险评估。案例包括试验动物特有的与肿瘤相关的蛋白质（案例研究3，d-柠檬烯）、实验室动物典型但人类不会出现的激素抑制导致的肿瘤后果（案例研究4，阿特拉津）以及相对于人类而言动物体内与化学物质相关的激素清除率提高（案例研究5，苯巴比妥）。在任何特定情况下，人类相关性分析对于所分析的化学物质-MOA-组织-终点组合具有高度特异性：对于给定的化学物质，不同的组织、不同的终点或替代的MOA可能会导致不同的人类相关性发现。通过提供一种使用MOA数据的系统方法，HRF为科学界提高癌症风险评估的预测能力、可靠性和透明度的整体努力提供了一种新工具。
