Validation of a Human In Vitro Vaginal Irritation Test

DESCRIPTION (provided by applicant): During Phase 1 research, the effects of 6 model test materials on a highly differentiated vaginal- ectocervical (VEC) tissue model were studied. Effects on tissue viability, structure, barrier function, and inflammatory cytokine release were monitored. Many of the assays gave results which supported one another and increased confidence in the in vitro results. For instance, histological damage and cytokine release paralleled losses in tissue viability. In addition, decreases in barrier function were measured when tissue viability decreased although the data indicated that barrier function was a more sensitive endpoint (i.e. decreases in barrier function occurred at lower concentrations that did not decrease tissue viability). Importantly, the one material which was mildly irritating in the rabbit vaginal irritation test induced significant decreases in tissue viability and barrier function and increased inflammatory mediator release. In addition, an economic analysis showed the in vitro method to be a cost-effective alternative to the currently used rabbit vaginal irritation test methodology. During Phase 2, the utility of the in vitro assay system will be further expanded to predict vaginal irritation following chronic, repeat exposure. Using the endpoints developed in Phase 1, a prediction model will be developed to accurately assess the in vivo vaginal irritation of test materials and formulations. The method will be transferred to outside contract testing labs and a multi-lab GLP validation study will be performed. In addition, the short and long term reproducibility of the assay will be assessed, and a high throughput version of the assay method will be developed. PUBLIC HEALTH RELEVANCE: A predictive test system for assessing the vaginal irritation potential of chemicals and formulations will have far reaching application in industries involved in women's care products, microbicide, contraceptives, excipient development, and topical pharmaceutical products. Evaluation of vaginal irritation is important to minimize chemical hazards to millions of women. The proposed human reconstructed tissue based system will provide a sensitive and validated assay method for screening of chemicals/formulations with vaginal irritation potential. Furthermore, the assay method will be cost effective and reduce the use of laboratory animals for experimentation.