The Windermere humic aqueous model using the toxicity function (WHAM‐FTOX) describes cation toxicity to aquatic organisms in terms of 1) accumulation by the organism of metabolically active protons and metals at reversible binding sites, and 2) differing toxic potencies of the bound cations. Cation accumulation (νi, in mol g−1) is estimated through calculations with the WHAM chemical speciation model by assuming that organism binding sites can be represented by those of humic acid. Toxicity coefficients (αi) are combined with νi to obtain the variable FTOX (= Σ αiνi) which, between lower and upper thresholds (FTOX,LT, FTOX,UT), is linearly related to toxic effect. Values of αi, FTOX,LT, and FTOX,LT are obtained by fitting toxicity data. Reasonable fits (72% of variance in toxic effect explained overall) were obtained for 4 large metal mixture acute toxicity experiments involving daphnids (Cu, Zn, Cd), lettuce (Cu, Zn, Ag), and trout (Zn, Cd, Pb). Strong nonadditive effects, most apparent in results for tests involving Cd, could be explained approximately by purely chemical competition for metal accumulation. Tentative interpretation of parameter values obtained from these and other experimental data suggests the following order of bound cation toxicity: H < Al < (Cu Zn Pb UO2) < (Cd Ag). Another trend is a strong increase in Cd toxicity relative to that of Zn as organism complexity increases (from bacteria to fish). Environ Toxicol Chem 2015;34:788–798. © 2014 SETAC