Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

Among women, breast cancer is the most prevalent form of cancer worldwide and has the second highest mortality rate of any cancer in the United States. The breast cancer related death rate is 40% higher in African American women compared to European American women. The incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which there is no targeted therapy, is approximately three times higher in non-Hispanic Black women (NHBW) compared to non-Hispanic White women (NHWW). The drivers of these differences in breast cancer incidence and mortality are still poorly understood, and likely lie in an interaction between genetic and environmental factors. Here, we aimed to identify chemical exposures which may play a role in breast cancer disparities. Using chemical biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and biological activity data from the EPAs ToxCast program, we assessed the toxicological profiles of chemicals with higher biomarker concentrations in US NHBW. We conducted a literature search to identify a gene set of breast cancer targets included in ToxCast to analyze the response of prioritized chemicals in these assays. Forty-three chemical biomarkers are significantly higher in NHBW. Investigation of these chemicals in ToxCast resulted in a total of 32,683 assays for analysis, 5,172 of which contained nonzero values for the concentration at which the dose-response fitted model reaches the cutoff considered "active" and the scaled top value of dose response curve. Of these chemicals BPA, PFOS, and thiram are most comprehensively assayed. 2,5-dichlorophenol, 1,4-dichlorobenzene, and methyl and propyl parabens had higher biomarker concentrations in NHBW and moderate testing and activity in ToxCast. The distribution of active concentrations for these chemicals in ToxCast assays are comparable to biomarker concentrations in NHBW. Through this integrated analysis, we have identified that multiple chemicals, including thiram, propylparaben, and p,p DDE, with disproportionate exposures in NHBW, have breast cancer associated biological activity at human exposure relevant doses.