Cancer Hazard Identification Integrating Human Variability: The Case of Coumarin.

Coumarin is a naturally occurring sweet-smelling benzopyrone that may be extracted from plants or synthesized for commercial uses. Its uses include as a flavoring agent, fragrance enhancer, and odor-masking additive. We reviewed and evaluated the scientific evidence on the carcinogenicity of coumarin, integrating information from carcinogenicity studies in animals with mechanistic and other relevant data, including data from toxicogenomic, genotoxicity, and metabolism studies, and studies of human variability of a key enzyme, CYP2A6. Increases in tumors were observed in multiple studies in rats and mice in multiple tissues. Our functional pathway analysis identified several common cancer-related biological processes/pathways affected by coumarin in rat liver following in vivo exposure and in human primary hepatocytes exposed in vitro. When coumarin 7-hydroxylation by CYP2A6 is compromised, this can lead to a shift in metabolism to the 3,4-epoxidation pathway and increased generation of electrophilic metabolites. Mechanistic data align with 3 key characteristics of carcinogens, namely formation of electrophilic metabolites, genotoxicity, and induction of oxidative stress. Considerations of metabolism, human variability in CYP2A6 activity, and coumarin hepatotoxicity in susceptible individuals provide additional support for carcinogenicity concern. Our analysis illustrates the importance of integrating information on human variability in the cancer hazard identification process.

Early life and adult exposure to isoflavones and breast cancer risk.

Soy and red-clover isoflavones are commonly consumed within the diet or as a dietary supplement due to a range of presumed beneficial health benefits. These isoflavones are thought to protect against heart diseases as well as breast and other types of cancer. Isoflavones are structurally similar to estrogens and may act as estrogen agonists or antagonists by binding to estrogen receptors. Because of an increased use of isoflavones in processed foods and dietary supplements as well as the greater consumption of soy products, dietary intakes of isoflavones are increasing in children and adolescents in North America. Estrogens are a known component of numerous hormone related cancers including breast cancer. It is with these facts in mind that we review the existing epidemiological and experimental animal studies for a resolution to a proposed correlation between increased isoflavone consumption and breast cancer. There is conflicting evidence from epidemiological, intervention and experimental animal studies regarding the chemopreventing effects of soy isoflavones in breast cancer. Isoflavones are weak estrogens and their effect depends upon the dose, time of exposure and species involved. It would, therefore, not be safe to indisputably accept soy or red-clover as a source of isoflavone resource to prevent breast cancer.