Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80176, 3508 TD Utrecht, The Netherlands.
Regul Toxicol Pharmacol. 2011 Oct;61(1):105-14. doi: 10.1016/j.yrtph.2011.06.007. Epub 2011 Jul 18.
The present paper aims at identifying strategies to increase the impact and applicability of alternative testing strategies in risk assessment. To this end, a quantitative and qualitative literature evaluation was performed on (a) current research efforts in the development of in vitro methods aiming for alternatives to animal testing, (b) the possibilities and limitations of in vitro methods for regulatory purposes and (c) the potential of physiologically-based kinetic (PBK) modeling to improve the impact and applicability of in vitro methods in risk assessment practice. Overall, the evaluation showed that the focus of state-of-the-art research activities does not seem to be optimally directed at developing in vitro alternatives for those endpoints that are most animal-demanding, such as reproductive and developmental toxicity, and carcinogenicity. A key limitation in the application of in vitro alternatives to such systemic endpoints is that in vitro methods do not provide so-called points of departure, necessary for regulators to set safe exposure limits. PBK-modeling could contribute to overcoming this limitation by providing a method that allows extrapolation of in vitro concentration-response curves to in vivo dose-response curves. However, more proofs of principle are required.
本文旨在确定增加替代测试策略在风险评估中的影响力和适用性的策略。为此，对（a）旨在替代动物测试的体外方法的开发的当前研究工作，（b）体外方法在监管方面的可能性和局限性，以及（c）生理相关动力学（PBK）模型在提高体外方法在风险评估实践中的影响力和适用性方面的潜力，进行了定量和定性文献评估。总体而言，评估结果表明，最先进的研究活动的重点似乎没有针对那些最需要动物实验的终点，如生殖和发育毒性以及致癌性，来优化开发体外替代方法。将体外替代方法应用于此类系统终点的一个主要限制是，体外方法无法提供所谓的起始点，而监管机构需要这些起始点来设定安全的暴露限值。PBK 建模可以通过提供一种方法来克服这一限制，该方法允许将体外浓度-反应曲线外推到体内剂量-反应曲线。然而，还需要更多的原理验证。
