Abstract 4792: Analysis of the relationship between experimentally induced rodent forestomach hyperplasia and tumorigenesis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Hyperplasia is an increase in cell number resulting from physiological processes such as irritation, or pathological processes like carcinogenesis. The difficulty in differentiating reactive versus preneoplastic (or dedicated) hyperplasia has been the subject of debate in the literature, especially in regard to prediction of human health risks following chronic chemical exposure. Squamous hyperplasia and neoplasia are frequently detected in the rodent forestomach (FS) following chronic oral administration of chemicals evaluated in rodent cancer bioassays. Molecular level mechanistic details related to FS hyperplasia progression are not available for a wide range of chemicals, despite the increasing need for this level of mechanistic understanding to support evaluations for human health risk. In order to facilitate further discussion on the use of rodent FS lesions in the estimation of cancer and noncancer reference values, a comparison of chemical hyperplasia versus tumor induction was performed. FS lesion classification and incidence data were obtained from rat and mouse gavage bioassays on over 50 chemicals from National Toxicology Program (NTP) 2-year bioassays that reported dose-related increases in FS hyperplastic or neoplastic lesions in one or more rodent sex/strain combinations tested. Chemical effects were tabulated and sorted by strain, sex, genotoxicity assay results and irritation effects, and the relationship between FS hyperplasia and FS tumor (e.g., squamous cell papilloma or carcinoma) induction was analyzed using grouped animal data. When considering chemicals with positive results in genotoxicity assays, FS tumors positively correlated with FS hyperplasia incidence in both rats and mice. Increased incidence of FS hyperplasia was not correlated with FS tumors in animals exposed to chemicals that were negative for genotoxicity and irritation. The potential results of this analysis may be useful in the evaluation of chemicals with limited chronic bioassay data by informing predictions of long-term tumor formation based on chemical properties observable during short-term animal or in vitro studies (e.g., genotoxicity, irritation). The views expressed in this abstract are those of the authors and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency. Citation Format: Jason M. Fritz, Maureen R. Gwinn. Analysis of the relationship between experimentally induced rodent forestomach hyperplasia and tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4792. doi:10.1158/1538-7445.AM2013-4792