A review of independent action compared to concentration addition as reference models for mixtures of compounds with different molecular target sites

Abstract

From a theoretical point of view, it has often been argued that the model of independent action (IA) is the most correct reference model to use for predicting the joint effect of mixtures of chemicals with different molecular target sites. The theory of IA, however, relies on a number of assumptions that are rarely fulfilled in practice. It has even been argued that, theoretically, the concentration addition (CA) model could be just as correct. In the present study, we tested the accuracy of both IA and CA in describing binary dose-response surfaces of chemicals with different molecular targets using statistical software. We compared the two models to determine which best describes data for 158 data sets. The data sets represented 98 different mixtures of, primarily, pesticides and pharmaceuticals tested on one or several of seven test systems containing one of the following: Vibrio fischeri, activated sludge microorganisms, Daphnia magna, Pseudokirchneriella subcapitata, Lemna minor, Tripleurospermum inodorum, or Stellaria media. The analyses showed that approximately 20% of the mixtures were adequately predicted only by IA, 10% were adequately predicted only by CA, and both models could predict the outcome of another 20% of the experiment. Half of the experiments could not be correctly described with either of the two models. When quantifying the maximal difference between modeled synergy or antagonism and the reference model predictions at a 50% effect concentration, neither of the models proved significantly better than the other. Thus, neither model can be selected over the other on the basis of accuracy alone.

Cadmium, lead and their mixtures with copper: Paracentrotus lividus embryotoxicity assessment, prediction, and offspring quality evaluation

“…The interaction of metals changed in relation to the concentrations employed in mixture. The variations in the type of combined effects for the different proportions of a mixture have been reported in literature (Cedergreen et al 2008;Fernandez and Beiras 2001;Otitoloju 2002). Moreover the deviation from predicted combined effects depend on the composition of mixture (Jonker et al 2005).…”

“…Secondary modes of action, uptake kinetics, transportation, metabolism, compartment, and excretion of the chemicals are among the processes that were not considered by the models but that have potentially large impacts on the joint effects (Cedergreen et al 2008).…”

“…Thus, the prediction of mixture toxicity on the basis of the pharmacological mode of action of the toxicant may lead to wrong conclusions when we deal with more complex biological systems such as whole organisms (Bellas 2008). Secondary modes of action, uptake kinetics, transportation, metabolism, and excretion of the chemicals are among the processes that were not considered by the models but that have potentially large impacts on the joint effects (Cedergreen et al 2008).…”

A metabolomics based test of independent action and concentration addition using the earthworm Lumbricus rubellus

“…For accurate risk assessment however, an important challenge is to understand and predict the consequences of multiple chemical exposures in the natural environment at relevant concentrations. There are currently two established models that can be used to describe the results of exposures to non-interactive mixtures: concentration addition (CA) and independent action (IA) (Cedergreen et al 2008). The CA model relies on the assumption that substances in a mixture have similar mechanisms of action and that they work through the same molecular target.…”

Effects on the Photosynthetic Activity of Algae after Exposure to Various Organic and Inorganic Pollutants: Review

“…Mixture toxicity studies focused on single species [85,86], natural communities in laboratory experiments [3,82,91], or outdoor microcosms and mesocosms [83,[92][93][94] data. Many reviews and critical analysis have shown that synergistic interactions within pesticide mixtures and realistic low-dose chemical mixtures in species are a rather rare phenomenon, constituting very low percentages of the tested mixture combinations and often occurs at high concentrations [87,[95][96][97][98][99][100][101]. According to the results of a comprehensive systematic review in which cocktail effects and synergistic interactions of chemicals in mixtures were predicted, synergy phenomena occurred only in 7% of the 194 binary pesticide mixtures included in the data compilation on frequency [101] (the database of Belden et al [98] provided data on 207 pesticide mixtures of which 194 were binary and another 13 consisted of more than two pesticides).…”