Moser Virginia C, Walls Isabel, Zoetis Tracey
Neurotoxicology Division/NHEERL/ORD, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Int J Toxicol. 2005 Mar-Apr;24(2):87-94. doi: 10.1080/10915810590936355.
Laboratory animal studies designed to assess the effects of exposure of a test substance during postnatal development are commonly utilized in basic research and to evaluate potential hazard to children for chemical and pharmaceutical regulation. Direct dosing, defined here as the administration of a test substance directly to a preweaning mammal, has been identified as a useful tool that can be used in the conduct of such studies for regulatory purposes. The International Life Sciences Institute Risk Science Institute (ILSI RSI) convened an Expert Working Group to develop guidance on the design and implementation of direct dosing regulatory studies on preweaning mammals, which was published as an ILSI monograph in 2003 (Zoetis and Walls, Principles and Practices for Direct Dosing of Pre-Weaning Mammals in Toxicity Testing and Research, Washington, DC: ILSI Press, 2003). A summary of the Working Group conclusions regarding direct dosing studies with laboratory rodents are presented here, although the ILSI monograph also includes rabbits, canines, swine and nonhuman primates. Issues to be considered when designing the protocol include selection of the test species, the route of administration, dose levels, and the timing of dosing. Knowledge of the maturational status of the test species and information on critical windows of development are important in creating a valid study design. Most common routes of administration (e.g., oral, inhalation, injection) are possible with typical laboratory species; however, adjustments may be necessary due to practical considerations. Information on the pharmacokinetic profile in young animals versus adults and in the test species versus humans is very useful for determining dosing parameters. The conduct of the study and the interpretation of the data will be improved by an understanding of confounding factors as well as statistical and biological issues specific for postnatal studies. Ultimately, the success of the study will depend upon careful preparation, including thorough training of the technical staff.
旨在评估产后发育期间受试物质暴露影响的实验动物研究，常用于基础研究以及评估化学和药物监管中对儿童的潜在危害。直接给药，在此定义为直接给未断奶哺乳动物施用受试物质，已被确定为一种有用的工具，可用于此类监管目的研究。国际生命科学研究所风险科学研究所（ILSI RSI）召集了一个专家工作组，以制定关于未断奶哺乳动物直接给药监管研究设计和实施的指南，该指南于2003年作为ILSI专著出版（Zoetis和Walls，《未断奶哺乳动物毒性测试和研究中的直接给药原则与实践》，华盛顿特区：ILSI出版社，2003年）。尽管ILSI专著还包括兔子、犬类、猪和非人灵长类动物，但此处介绍了工作组关于实验室啮齿动物直接给药研究结论的摘要。设计方案时要考虑的问题包括受试物种的选择、给药途径、剂量水平和给药时间。了解受试物种的成熟状态以及发育关键期的信息对于创建有效的研究设计很重要。对于典型的实验物种，大多数常见的给药途径（如口服、吸入、注射）都是可行的；然而，出于实际考虑可能需要进行调整。关于幼龄动物与成年动物以及受试物种与人类的药代动力学特征信息，对于确定给药参数非常有用。了解混杂因素以及产后研究特有的统计和生物学问题，将有助于改进研究的实施和数据的解释。最终，研究的成功将取决于精心准备，包括对技术人员的全面培训。
