Guyton Kathryn Z, Barone Stanley, Brown Rebecca C, Euling Susan Y, Jinot Jennifer, Makris Susan
National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.
J Toxicol Environ Health B Crit Rev. 2008 Jan;11(1):16-31. doi: 10.1080/10937400701600321.
Mode of action (MOA) information is increasingly being applied in human health risk assessment. The MOA can inform issues such as the relevance of observed effects in laboratory animals to humans, and the variability of response within the human population. Several collaborative groups have developed frameworks for analyzing and utilizing MOA information in human health risk assessment of environmental carcinogens and toxins, including the International Programme on Chemical Safety, International Life Sciences Institute, and U.S. Environmental Protection Agency. With the goal of identifying gaps and opportunities for progress, we critically evaluate several of these MOA frameworks. Despite continued improvement in incorporating biological data in human health risk assessment, several notable challenges remain. These include articulation of the significant role of scientific judgment in establishing an MOA and its relevance to humans. In addition, binary (yes/no) decisions can inappropriately exclude consideration of data that may nonetheless be informative to the overall assessment of risk. Indeed, the frameworks lack a broad consideration of known causes of human disease and the potential for chemical effects to act additively with these as well as endogenous background processes. No integrated analysis of the impact of multiple MOAs over the same dose range, or of varying MOAs at different life stages, is included. Separate consideration of each MOA and outcome limits understanding of how multiple metabolites, modes, and toxicity pathways contribute to the toxicological profile of the chemical. An extension of the analyses across outcomes with common modes is also needed.
作用机制（MOA）信息越来越多地应用于人类健康风险评估。作用机制能够为一些问题提供参考，比如实验动物中观察到的效应与人类的相关性，以及人群中反应的变异性。几个合作小组已经开发出在环境致癌物和毒素的人类健康风险评估中分析和利用作用机制信息的框架，包括国际化学品安全计划、国际生命科学研究所和美国环境保护局。为了找出进展中的差距和机会，我们严格评估了其中几个作用机制框架。尽管在将生物学数据纳入人类健康风险评估方面不断取得进步，但仍存在一些显著挑战。这些挑战包括明确科学判断在确定作用机制及其与人类的相关性方面的重要作用。此外，二元（是/否）决策可能会不适当地排除对可能仍有助于总体风险评估的数据的考虑。事实上，这些框架缺乏对人类疾病已知病因以及化学效应与这些病因和内源性背景过程相加作用可能性的广泛考虑。没有对同一剂量范围内多种作用机制的影响，或不同生命阶段不同作用机制的影响进行综合分析。对每种作用机制和结果的单独考虑限制了对多种代谢物、作用方式和毒性途径如何促成化学品毒理学特征的理解。还需要对具有共同作用方式的结果进行扩展分析。
