Conflicting views on chemical carcinogenesis arising from the design and evaluation of rodent carcinogenicity studies
Conflicting views on chemical carcinogenesis arising from the design and evaluation of rodent carcinogenicity studies
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DOI：
10.1289/ehp.9989
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发表时间：
2008-01-01
影响因子：
10.4
通讯作者：
Bucher, John R.
中科院分区：
文献类型：
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作者：
Melnick, Ronald L.;Thayer, Kristina A.;Bucher, John R.
对于基于动物致癌性数据的环境制剂对人类癌症风险的评估，经常表达出相互矛盾的观点；这主要是因为与从实验动物研究到人类环境的毒理学结果的推断相关的不确定性。在这些不确定性的背后，是与实验如何设计、假设如何被严格检验以及断言在多大程度上超出实际结果有关的问题。国家和国际卫生机构认为，在进行良好的实验动物研究中发现的致癌性，是人类潜在致癌风险的证据。当一种特定制剂的致癌性阳性和阴性数据都存在时，或者当不完整的机制数据表明反应可能存在物种差异时，就会出现争议。本文讨论了可能导致不同结果的实验设计和评估问题。为了作为评估环境制剂致癌潜力的可靠数据来源，实验研究必须包括a)对研究终点敏感的动物模型；b)对制剂和投放剂量的详细描述；c)具有挑战性的剂量和暴露时间(大鼠和小鼠至少2年)；d)每剂量组有足够的动物数量，能够检测到真正的效果；e)多剂量组，以便于描述剂量-反应关系，f)完成和同行评议的组织病理学评估；g)根据生存调整的肿瘤发病率进行配对比较和分析。药代动力学模型和机制假说可以提供对该制剂的生物学行为的洞察；然而，在用于评估人类癌症风险之前，它们必须经过充分的测试。
Conflicting views have been expressed frequently on assessments of human cancer risk of environmental agents based on animal carcinogenicity data; this is primarily because of uncertainties associated with extrapolations of toxicologic findings from studies in experimental animals to human circumstances. Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings. National and international health agencies regard carcinogenicity findings in well-conducted experimental animal studies as evidence of potential carcinogenic risk to humans. Controversies arise when both positive and negative carcinogenicity data exist for a specific agent or when incomplete mechanistic data suggest a possible species difference in response. Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article. To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose-response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence. Pharmacokinetic models and mechanistic hypotheses may provide insights into the biological behavior of the agent; however, they must be adequately tested before being used to evaluate human cancer risk.