Based on previous research on the acute toxicity of major ions (Na+, K+, Ca2+, Mg2+, Cl, SO42, and HCO3/CO32) to C. dubia, two mathematical models were developed for predicting the LC50 for any ion mixture, excluding those dominated by K toxicity. One model addresses a mechanism of general ion toxicity to which all ions contribute, and describes osmolarity-based LC50s as a function of Ca activity. The other model addresses a mechanism specifically related to Mg and Ca to apply when such toxicity exceeds general ion toxicity, and describes LC50s as a function of Mg and Ca activities. Both models track well the observed LC50s from past research used in model development, but also successfully predicted LC50s from new toxicity tests on synthetic mixtures of ions emulating chemistries of various ion-enriched effluents and receiving waters. Because of the complexities of relating LC50s to chemical activities and osmolarity, simplified models based directly on ion concentrations were also developed and found to provide useful predictions. These models were also determined to provide better performance than a previously-published model for major ion toxicity.