Ingested inorganic arsenic is strongly associated with a wide spectrum of adverse health outcomes. We propose a bioaccumulation and the Weibull model-based epidemiological framework to accurately estimate the reference arsenic intake guideline for tilapia consumption and tilapia-cultured water arsenic concentration based on bioaccumulations of tilapia and gender/age/cancer-specific epidemiological data from the arseniasis-endemic area in Taiwan. Our results show a positive relationship between arsenic exposure and age/gender- and cancer-specific cumulative incidence ratio using Weibull dose-response model. Based on male bladder cancer with an excess lifetime cancer risk of 10(-4), we estimate the reference tilapia inorganic arsenic guideline value to be 0.084 microg g(-1) dry wt based on the suggested daily consumption rate of 120 gd(-1). Our findings show that consumption of tilapia in a blackfoot disease (BFD)-endemic area poses no significant cancer risk (excess cancer risks ranging from 3.4 x 10(-5) to 9.3 x 10(-5)), implying that people in BFD-endemic areas are not readily associated with higher fatalities for bladder cancer exposed from tilapia consumption. We are confident that our model can be easily adapted for other aquaculture species, and encourage risk managers to use the model to evaluate the potential population-level long-term low-dose cancer risks. We conclude that, by integrating the bioaccumulation concept and epidemiological investigation of humans exposed to arsenic, we can provide a scientific basis for risk analysis to enhance risk management strategies.