It is unclear whether the United States Environmental Protection Agency (US EPA) method can accurately assess heavy metal risks in high-Se areas. Herein, a black shale outcropping in Enshi County, China, was taken as the study area, and a carbonate outcropping in Lichuan County was the control area. Selenium and associated heavy metal concentrations in rock, soil, rice, human blood and urine samples and human sensitive hepatic and renal biomarkers were measured. The results showed that the contents of selenium, cadmium, molybdenum and copper in the study area were 3.68 ± 2.72 μg/g, 2.65 ± 1.42 μg/g, 16.3 ± 15.5 μg/g, and 57.3 ± 17.6 μg/g, respectively, in soil (n = 47) and 1.072 ± 0.924 μg/g, 0.252 ± 0.310 μg/g, 2.800 ± 2.167 μg/g, and 10.91 ± 27.42 μg/g, respectively, in rice (n = 47). The daily adult intake levels of selenium, cadmium and molybdenum from rice consumption in the study area (exposure group) exceed the recommended tolerance values in China. According to the US EPA method, these environmental media pose a significant risk to human health. However, in the exposure group (n = 111), the median levels of the sensitive hepatic biomarkers alanine aminotransferase (18 U/L), aspartate aminotransferase (28 U/L) and total bilirubin (10.9 μmol/L) and the sensitive renal biomarkers serum creatinine (70.1 μmol/L), urinary nitrogen (5.73 mmol/L) and uric acid (303.80 μmol/L) were within reference ranges and had values equivalent to those of the control group (P > 0.05). The elements tended to differentiate during migration from one medium to another. Due to the complex interaction between selenium and heavy metals, a survey of human health indicators is indispensable when the US EPA method is used to assess the heavy metal risks in high-Se areas. The recommended molybdenum tolerable intake in the U.S. (2000 μg/d) is reasonable based on a comparison.