Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.

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.

Bisphenol A (BPA) is a high production volume chemical that has been used for decades in numerous consumer and industrial applications. Daily exposure to B

Vinyl acetate (VA) is a synthetic chemical that can be metabolized to form the carcinogen acetaldehyde (AA). This paper summarizes the key evidence relevant to the evaluation of VA’s carcinogenicity. We conducted a literature search and reviewed data relevant to the carcinogenicity of VA using a systematic approach. The literature reviewed included epidemiological studies, animal carcinogenicity studies, pharmacokinetic and metabolism studies, as well as studies relevant to the key characteristics of carcinogens. The body of epidemiological evidence includes several occupational studies with significant limitations and one prospective cohort study that assessed ambient air exposure to VA and breast cancer risk. The evidence from animal carcinogenicity studies is considered strong. VA induced tumors in a number of tissues across different strains of rats and mice in both sexes, via two exposure routes (inhalation and drinking water). Some tumor findings showed dose-related trends and were not limited to site-of-entry tissues. VA’s metabolic link to AA strengthens the evidence by providing biological plausibility: both chemicals induced many of the same DNA adducts, genotoxicity endpoints, and tumor types at many of the same sites. In addition, VA demonstrates three of the ten key characteristics of carcinogens in that it can be metabolically activated to be electrophilic, is genotoxic, and induces cell proliferation. Our review of VA’s carcinogenicity shows compelling evidence in animal cancer bioassays with supporting mechanistic data, including the formation of reactive compounds and DNA adducts, evidence of genotoxicity including clastogenicity and DNA damage, and the ability to induce cell proliferation and pre-neoplastic lesions. The metabolic link to AA was an important consideration.