Application of the Key Characteristics of Carcinogens to Bisphenol A

Abstract

The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act.

Keywords: Bisphenol A (BPA); cell proliferation; chronic inflammation; epigenetic alterations; genotoxicity; key characteristics (KCs) of carcinogens; mechanisms of carcinogenesis; oxidative stress; reactive and bioactive metabolites; receptor-mediated effects.