John Wiley & Sons, Ltd.

Metal mixture modeling evaluation project: 3. Lessons learned and steps forward

A comparison of 4 metal‐mixture toxicity models (that were based on the Biotic Ligand Model and WHAM‐FTOX) was presented in the previous paper. In the present study, a streamlined version of the 4 models was developed and applied to multiple datasets and test conditions to examine key assumptions and calibration strategies that are crucial in modeling metal‐mixture toxicity. Results show that: (i) a single binding site on or in the organism was a useful and oftentimes sufficient framework for predicting metal toxicity, (ii) a linear free energy relationship (LFER) for bidentate binding of metals and cations to the biotic ligand provided a good first estimate of binding coefficients, (iii) although adjustments in metal binding coefficients or adjustments in chemical potency factors can both be used in model calibration for single‐metal exposures, changing metal binding coefficients or chemical potency factors had different effects on model predictions for metal mixtures, and (iv) selection of a mixture toxicity model (based on concentration addition or independent action) was important in predicting metal‐mixture toxicity. In moving forward, efforts should focus on reducing uncertainties in model calibration, including development of better methods to characterize metal binding to toxicologically‐active binding sites, conducting targeted exposure studies to advance the understanding of metal‐mixture toxicity, and further developing LFERs and other tools to help constrain the model calibration. This article is protected by copyright. All rights reserved

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