Andersen M E, Meek M E, Boorman G A, Brusick D J, Cohen S M, Dragan Y P, Frederick C B, Goodman J I, Hard G C, O'Flaherty E J, Robinson D E
Department of Environmental Health, Colorado State University, Fort Collins, USA.
Toxicol Sci. 2000 Feb;53(2):159-72. doi: 10.1093/toxsci/53.2.159.
An expert panel was convened to evaluate the U.S. Environmental Protection Agency's "Proposed Guidelines for Carcinogen Risk Assessment" through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel's activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical's mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5 ) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted.
召集了一个专家小组，通过将美国环境保护局的《致癌物风险评估拟议指南》应用于氯仿（CHCl3）和二氯乙酸（DCA）的数据集来对其进行评估。该小组还对将这些指南应用于这些特定化合物时所察觉到的优势和局限性发表了评论。该小组活动的后一个方面是本观点的重点。该小组对这些拟议指南的演变非常热情，这些指南代表了与美国环境保护局早期癌症风险评估指南相比向前迈出的重要一步。这些新指南提供了考虑各种科学数据的余地，并在剂量反应评估中允许相当大的灵活性，这取决于化学物质的作用方式。它们是将最新科学纳入致癌物风险评估的非常有用的模板。此外，新指南促进了癌症风险评估和非癌症风险评估方法的协调统一。虽然关于由作用方式的确定所产生的定性决策的新指南相对简单明了，但对各种风险评估选项的定量实施的描述需要进一步完善。需要澄清的具体领域包括：（1）判断任何特定作用方式的证据权重是否充分的决策标准；（2）作用方式在指导毒代动力学、基于生物学或特定案例模型的开发中的作用；（3）作用方式和其他技术考虑因素为暴露边际计算提供指导的方式；（4）风险管理者与风险评估者在评估暴露边际方面的相对作用；以及（5）作用方式在协调癌症和非癌症风险评估方法方面的影响。这些要点作为对任何修订的改进建议进行了详细阐述。一般来说，纳入特定化学物质的定量评估示例将加强这些指南。显然，任何修订都应保留这些指南草案中对单个化合物使用科学信息的灵活性的强调，同时改进对这些作用方式数据的组织和解释过程的描述。
