The derivation of protective values for aquatic life can be enhanced by the development and use of bioavailability models. Recent advances to metals bioavailability modeling are applicable to other analyte groups and should be widely considered. We conducted a meta‐analysis of the available aquatic toxicity literature for fluoride to evaluate the utility of hardness, alkalinity, and chloride as toxicity‐modifying factors (TMFs) in empirical bioavailability models of freshwater taxa. The resulting optimal multiple linear regression model predicting acute fluoride toxicity to the invertebrate Hyalella azteca included all three TMFs (observed vs. predicted 50% lethal concentrations, R 2 = 0.88) and the optimal model predicting toxicity to the fish Oncorhynchus mykiss included alkalinity and hardness (R 2 = 0.37). At >20 mg/L chloride, the preliminary final acute values for fluoride were within 1 order of magnitude and ranged from approximately 18.1 to 56.3 mg/L, depending on water chemistry. Sensitivity of H. azteca to low‐chloride conditions increased model uncertainty when chloride was <20 mg/L. Because of limited toxicity data, chronic bioavailability models were not developed, and final chronic values were derived using an acute‐to‐chronic ratio (ACR) approach. Accounting for TMFs, the geometric mean ACR was 5.4 for fish and invertebrate taxa (n = 6). The present assessment highlights the need to expand bioavailability modeling to include inorganic anions, particularly fluoride, and demonstrates that existing promulgated protective values for fluoride are likely overly conservative. More toxicological studies are recommended to further refine multivariate empirical bioavailability models for inorganic anions. Environ Toxicol Chem 2022;41:396–409. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.