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Many human activities increase concentrations of major geochemical ions (Na+1, K+1, Ca+2, Mg+2, Cl-1, SO4-2, and HCO3-1/CO3-2) in freshwater systems, and can thereby adversely affect aquatic life. Such effects involve several toxicants, multiple toxicity mechanisms, various ion interactions, and widely varying ion compositions across different water bodies. Previous studies of individual salt toxicities have defined some useful relationships; however, adding single salts to waters results in atypical compositions and does not fully address mixture toxicity. To better understand mechanisms and interactions for major ion toxicity, 29 binary mixture experiments, each consisting of 7 to 8 toxicity tests, were conducted on the acute toxicity of major ion salts and mannitol to Ceriodaphnia dubia. These tests showed multiple mechanisms of toxicity, including: 1) nonspecific ion toxicity, correlated with osmolarity and to which all ions contribute; and 2) cation-dependent toxicities for potassium (K), magnesium (Mg), and calcium (Ca) best related to their chemical activities. These mechanisms primarily operate independently, except for additive toxicity of Mg-dependent and Ca-dependent toxicities. These mixture studies confirmed ameliorative effects of Ca on sodium (Na) and Mg salt toxicities and of Na on K salt toxicity, and further indicated lesser ameliorative effects of Ca on K salt toxicity and Mg on Na salt toxicity. These results provide a stronger basis for assessing risks from the complex mixtures of ions found in surface waters. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.