Validation of a Human In Vitro Vaginal Irritation Test

说明(由申请人提供)：女性生殖道暴露于杀精剂、药物、杀微生物剂、女性卫生和其他阴道护理产品(VCP)中所含的各种化学物质可引起炎症或组织损伤，从而危及妇女的健康。VCP对阴道上皮的干扰也会增加获得性传播感染(包括HIV-1)的风险。目前的阴道刺激性/毒性测试主要是使用动物模型进行的，这既耗时又昂贵。此外，最常用的兔阴道毒性模型的结果并不总是与人类的反应相关。到目前为止，还没有经过验证的人体体外阴道刺激方法。本研究项目将开发这样一种测试方法。第一阶段研究将预先验证Mattek的器官型阴道-宫颈外(VEC)组织模型，用于识别现有或新开发的VCP的潜在危险。体外检测将包括组织活力、结构损伤、屏障功能和细胞因子释放测量。平行实验将在急性兔阴道刺激试验中进行，使用一套定义良好的模型试验材料。体内和体外数据的相关性将导致建立一种灵敏可靠的体外阴道刺激试验方法。在第二阶段，该测试方法将在多中心的GLP研究中接受正式验证。用于评估化学品/制剂的刺激性的预先验证的体外阴道器官组织模型将在涉及阴道护理产品、杀菌剂、杀精剂以及其他女性卫生和局部药物产品的行业中有广泛的应用。评估刺激性程度对于将暴露于局部应用产品的妇女的危险降至最低很重要。拟议的人体组织化验将提供一种灵敏和具体的、省时的方法，以降低成本筛选大量化学品/制剂。

DESCRIPTION (provided by applicant): Exposure of female reproductive tract to the various chemical agents contained within spermicides, medicaments, microbicides, feminine hygiene and other vaginal care products (VCP) can cause inflammation or tissue damage and thus endanger the health of women. Perturbation of the vaginal epithelium by VCP can also increase the risk of acquiring sexually transmitted infections including HIV-1. Current vaginal irritation/toxicity tests are primarily performed using animal models which are time consuming and costly. Furthermore, results from the most commonly used rabbit vaginal toxicity model do not always correlate with human responses. To date, no validated, human in vitro vaginal irritation method exists. This research project will develop such a test method. Phase I research will prevalidate MatTek's organotypic vaginal-ectocervical (VEC) tissue model for use in identifying potential hazard of existing or newly developed VCP. In vitro assays will include tissue viability, structural damage, barrier function, and cytokine release measurements. Parallel experiments will be performed in an acute rabbit vaginal irritation assay using a well defined set of model test materials. Correlation of the in vivo and in vitro data will result in the development of a sensitive and reliable in vitro vaginal irritation test method. During Phase II, the test method will undergo formal validation in a multi-center, GLP study. A prevalidated in vitro vaginal organotypic tissue model for assessing the irritation potential of chemicals/ formulations will have far reaching application in industries involved in vaginal care products, microbicides, spermicides, and other feminine hygiene and topical pharmaceutical products. Evaluation of irritancy levels is important to minimize hazards in women exposed to topically applied products. The proposed human tissue based assay will provide a sensitive and specific time-efficient method to screen a large number of chemicals/formulations at a reduced cost.