Ono Atsushi
Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 2010(128):44-9.
Tens of thousands of existing chemicals have been widely used for manufacture, agriculture, household and other purposes in worldwide. Only approximately 10% of chemicals have been assessed for human health hazard. The health hazard assessment of residual large number of chemicals for which little or no information of their toxicity is available is urgently needed for public health. However, the conduct of traditional toxicity tests which involves using animals for all of these chemicals would be economically impractical and ethically unacceptable. (Quantitative) Structure-Activity Relationships [(Q)SARs] are expected as method to have the potential to estimate hazards of chemicals from their structure, while reducing time, cost and animal testing currently needed. Therefore, our studies have been focused on evaluation of available (Q)SAR systems for estimating in vivo repeated toxicity on the liver. The results from our preliminary analysis showed the distribution for LogP of the chemicals which have potential to induce liver toxicity was bell-shape and indicating the possibility to estimate liver toxicity of chemicals from their physicochemical property. We have developed (Q)SAR models to in vivo liver toxicity using three commercially available systems (DEREK, ADMEWorks and MultiCASE) as well as combinatorial use of publically available chemoinformatic tools (CDK, MOSS and WEKA). Distinct data-sets of the 28-day repeated dose toxicity test of new and existing chemicals evaluated in Japan were used for model development and performance test. The results that concordances of commercial systems and public tools were almost same which below 70% may suggest currently attainable knowledge of in silico estimation of complex biological process, though it possible to obtain complementary and enhanced performance by combining predictions from different programs. In future, the combinatorial application of in silico and in vitro tests might provide more accurate information which support regulatory decisions. At the same time, an appropriate strategy to use (Q)SAR for of the efficiency and accuracy in chemical management is necessary.
数以万计的现有化学品已在全球范围内广泛用于制造、农业、家庭及其他用途。仅有约10%的化学品进行了人体健康危害评估。出于公共卫生的迫切需求，急需对大量毒性信息很少或没有的残留化学品进行健康危害评估。然而，对所有这些化学品进行传统毒性测试（包括使用动物）在经济上不切实际且在伦理上不可接受。（定量）构效关系[(Q)SARs]有望成为一种从化学品结构估计其危害的方法，同时减少目前所需的时间、成本和动物试验。因此，我们的研究重点是评估可用的(Q)SAR系统，以估计肝脏的体内重复毒性。我们初步分析的结果表明，有可能诱导肝脏毒性的化学品的LogP分布呈钟形，这表明有可能从其物理化学性质估计化学品的肝脏毒性。我们使用三种商业可用系统（DEREK、ADMEWorks和MultiCASE）以及公开可用的化学信息学工具（CDK、MOSS和WEKA）的组合开发了用于体内肝脏毒性的(Q)SAR模型。在日本评估的新化学品和现有化学品的28天重复剂量毒性测试的不同数据集用于模型开发和性能测试。商业系统和公共工具的一致性几乎相同且低于70%的结果可能表明，目前通过计算机模拟估计复杂生物过程所能获得的知识水平，尽管通过组合不同程序的预测有可能获得互补和增强的性能。未来，计算机模拟和体外测试的组合应用可能会提供更准确的信息，以支持监管决策。同时，有必要采取适当策略使用(Q)SAR来提高化学品管理的效率和准确性。
