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首页> 外文期刊>Toxicologic pathology >A perspective on current and future uses of alternative models for carcinogenicity testing.
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A perspective on current and future uses of alternative models for carcinogenicity testing.

机译：对当前和将来使用替代模型进行致癌性测试的观点。

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This perspective is based upon the data presented at the International Life Sciences Institute (ILSI), Health and Environmental Sciences Institute Workshop on the Evaluation of Alternative Methods for Carcinogenicity Testing (ILSI Workshop). It is important to understand that all models discussed at the Workshop have limitations and that they are not designed to be employed as stand-alone assays. Although they may have other, appropriate applications. I do not recommend use of the SHE cell assay and the Tg.AC model for the regulatory purposes of a safety assessment. In my view, the neonatal mouse, p53+/-, XPA-/-, XPA-/- and p53+/-, and the rasH2 models can, as a component of an overall assessment, provide information on potential carcinogenicity of a chemical that is appropriate for consideration in a regulatory context. Generally, these models exhibit the ability to detect genotoxic compounds. In most cases these compounds would be detected in a standard battery of genotoxicity tests and, therefore, quite often the use of an alternative is not necessary. Actually, I believe that a bioassay in rats will suffice most of the time, that is, in my view, a routine bioassay in mice is not necessary. Specific circumstances where data obtained from one of the "recommended" alternative models might be helpful are discussed. With regard to lessons for the future, there is a particular need for models that are responsive to chemicals that exhibit a nongenotoxic mode of action. Additionally, new models will continue to be developed and their half-life will likely be substantially shorter than the time required for traditional validation. The development of enhanced paradigms for validation should be a priority so that improved safety assessment decisions can be made more quickly. However, while evaluating and validating such models, it is important to consider the fundamental issues, for example, rational dose selection, evaluation of mode of action in the context of dose-response relationships including the existence of thresholds and secondary mechanisms, and species-to-species extrapolation. The alternatives to carcinogenicity testing project was a very major undertaking. In addition to the valuable information provided, it serves to illustrate the value of cooperation between academia, government, and industry. Furthermore, the involvement of the International Life Sciences Institute as the overall organizing, facilitating umbrella was crucial for the success of the project.
机译：此观点基于国际生命科学研究所（ILSI），健康与环境科学研究所关于致癌性测试替代方法评估的研讨会（ILSI研讨会）上提供的数据。重要的是要理解，在研讨会上讨论的所有模型都具有局限性，并且它们并非旨在用作独立的检测方法。尽管它们可能还有其他适当的应用程序。我不建议将SHE细胞测定法和Tg.AC模型用于安全评估的监管目的。在我看来，新生小鼠p53 +/-，XPA-/-，XPA-/-和p53 +/-和rasH2模型可以作为整体评估的一部分，提供有关化学物质潜在致癌性的信息。适合在监管环境中考虑。通常，这些模型表现出检测遗传毒性化合物的能力。在大多数情况下，这些化合物会在一组标准的遗传毒性试验中被检测到，因此，通常无需使用替代方法。实际上，我相信大鼠的生物测定在大多数情况下就足够了，也就是说，在我看来，小鼠的常规生物测定是不必要的。讨论了从“推荐”替代模型之一获得的数据可能有用的特定情况。关于将来的经验教训，特别需要对显示非遗传毒性作用方式的化学物质敏感的模型。此外，将继续开发新模型，其半衰期可能会比传统验证所需的时间大大缩短。开发用于验证的增强范例应成为优先事项，以便可以更快地做出改进的安全评估决策。但是，在评估和验证此类模型时，重要的是要考虑一些基本问题，例如，合理的剂量选择，在剂量反应关系（包括阈值和二级机制的存在）以及物种-种外推法。致癌性测试项目的替代方法是一项非常艰巨的任务。除了提供的有价值的信息外，它还用于说明学术界，政府和行业之间合作的价值。此外，国际生命科学研究所作为整体组织，便利伞的参与对于该项目的成功至关重要。

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