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In vitro assays and high-throughput screening (HTS) tools are increasingly being employed as replacements for animal testing, but most concentration-response curves are still evaluated with models developed for animal testing. We argue that application of in vitro assays, particularly reporter gene assays, to environmental samples can benefit from a different approach to concentration-response modeling. First, cytotoxicity often occurs at higher concentrations, especially for weakly acting compounds and in complex environmental mixtures with many components. In these cases, specific effects can be masked by cytotoxicity. Second, for many HTS assays, low effect levels can be precisely quantified because of the low variability of controls in cell-based assays and the opportunity to run many concentrations and replicates when using high-density well-plate formats (e.g., 384 or more wells per plate). Hence, we recommend focusing concentration-response modeling on the lower portion of the concentration-response curve, which is approximately linear. Effect concentrations derived from low-effect level linear concentration-response models facilitate simple derivation of relative effect potencies and the correct application of mixture toxicity models in the calculation of bioanalytical equivalent concentrations. Environ Toxicol Chem 2018;37:2273-2280. (c) 2018 SETAC