Chronic fluoride-arsenic combined poisoning is a global public health problem. While the cause of the disease is clear, the pathogenesis is unknown. Given that there is no specific treatment, early prevention is particularly important. Biological exposure limits are designed to investigate the maximum allowable concentration of harmful effects from exogenous chemicals. To explore the biological exposure limits for mixed exposures of fluoride and arsenic, we compared the contents of fluorine and arsenic in the environmental media of the control and fluoride-arsenic combined exposure areas and analyzed the dose-effect and dose-response relationship between fluoride, arsenic and the key proteins of Wnt signaling pathways. The benchmark dose method was used to estimate the biological exposure limit for fluoride-arsenic combined exposure. The results showed that the content of fluoride in coal, clay, indoor air, outdoor air, chili and rice, as well as arsenic content in coal, clay, outdoor air, chili and rice was higher than that of the control. With the increase of fluoride and arsenic exposure levels, the glycogen synthase kinase 3β (GSK3β), β-catenin contents and the prevalence of Wnt/β-catenin signaling pathway antagonistic protein Dickkopf-1 (DKK1), GSK3β, Beta-catenin (β-catenin) gradually increased, but the content of DKK1 significantly decreased. Based on the Wnt signaling pathway, the biological exposure limit for fluoride-arsenic combined exposure was urinary fluoride of 0.52 mg·g-1 creatinine and urinary arsenic of 6.59 mg·g-1 creatinine. Our results had important guiding significance for early prevention of body damage caused by fluoride-arsenic combined poisoning.