Abstract
Current methods to assess the impact of chemical mixtures on organisms ignore the temporal dimension. The General Unified Threshold model for Survival (GUTS) provides a framework for deriving toxicokinetic–toxicodynamic (TKTD) models, which account for effects of toxicant exposure on survival in time. Starting from the classic assumptions of independent action and concentration addition, we derive equations for the GUTS reduced (GUTS-RED) model corresponding to these mixture toxicity concepts and go on to demonstrate their application. Using experimental binary mixture studies with Enchytraeus crypticus and previously published data for Daphnia magna and Apis mellifera, we assessed the predictive power of the extended GUTS-RED framework for mixture assessment. The extended models accurately predicted the mixture effect. The GUTS parameters on single exposure data, mixture model calibration, and predictive power analyses on mixture exposure data offer novel diagnostic tools to inform on the chemical mode of action, specifically whether a similar or dissimilar form of damage is caused by mixture components. Finally, observed deviations from model predictions can identify interactions, e.g., synergism or antagonism, between chemicals in the mixture, which are not accounted for by the models. TKTD models, such as GUTS-RED, thus offer a framework to implement new mechanistic knowledge in mixture hazard assessments.
Highlights
Human activities release a plethora of chemicals into the environment[1] that can lead to effects on nontarget organisms.The environmental risk assessment (ERA) for individual chemicals is established with robust methods, including experimental designs and data analysis methods in place.[2]While risk assessment may take a chemical-by-chemical approach, in practice, ecosystems are subject to many inputs from agricultural, industrial, and domestic sources
For all fits and predictions, we provided the model efficiency with the r2 and Akaike information criterion (AIC) value
The comparison of the mortality-related parameters for the chemicals is useful to choose between the damage addition (DA) and independent action (IA) and as a powerful tool to explore whether two chemicals may share the same mode of action
Summary
Human activities release a plethora of chemicals into the environment[1] that can lead to effects on nontarget organisms. Because chemicals can differ in their efficiency in causing damage, and because we worked with scaled damage, an additional model parameter, the weight factor W, needs to be applied to the substance-specific attributed scaled damage before these are summed This is similar to the concept of relative potency for mixture effects, which has been successfully used in the past for in vitro bioassays,[24] polychlorinated dibenzodioxins (toxic equivalency factors),[25] water quality criteria for herbicides with the same mode of action in surface water,[26] and QSAR models considering concentration addition.[27] The W factor is a new parameter that is constant over time, and it is fitted during the simultaneous fit of the single exposure data of both substances with the GUTS-RED damage addition model. The plot of the mortality parameters, the simultaneous fit of the single exposures, and prediction for the mixture effects together identify the DA model as more appropriate for this mixture with putative similar mode of action, consistent with our underlying theory for model development At this stage, a mixture toxicity test is required to deliver the ultimate proof about the chemical mode of action.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
