We investigated the interaction effects of cadmium, lead and four PAHs on the toxicity of arsenic and each other. A simulated in vitro human digestive system and human liver cell-based assays were employed to determine their respective bioaccessibility, uptake and toxicity of individual toxicants and mixtures of up to all seven chemicals. Under most environmental conditions, additive effect can be assumed when assessing bioaccessibility of mixed arsenic, cadmium and lead with or without polyaromatic hydrocarbons whilst hepatic uptake was less than additive for cadmium mixed with arsenic/lead/pyrene/benzo[a]pyrene. Toxicity in HepG2 cells including cytotoxicity, oxidative stress, genotoxicity and AhR (aryl hydrocarbon receptor) activation were determined. The interaction amongst mixtures vary depending on toxic endpoints, concentration and number of individual chemicals in the mixtures. Therefore, the traditional concentration addition or independent action model for health risk assessment may over or under estimate the risk of mixtures. This study has gained understanding of mixture interaction and helps to refine current risk assessment of mixed contaminants.