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

Cedergreen, Nina; Christensen, Anne Illemann; Kamper, Anja; Kudsk, Per; Mathiassen, Solvejg K.; Streibig, J. C.; Sørensen, Helle

doi:10.1897/07-474

Cited by 83 publications

(132 citation statements)

References 27 publications

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“…In addition, mechanisms of action are often unknown. In this regard, toxicology and ecotoxicology fields have become the focus for non-lethal end points (Cedergreen et al 2008). These tests measure gradual end points such as growth, morphological and behavioral changes which are all quantitative and therefore do not fit the theoretical assumptions of IA (Faust et al 2003;Gessner 1988).…”

Section: Classical Interactive Hypothesis: Identification Of the Modementioning

confidence: 99%

“…The importance of the assumptions of CA concerning both the degree of similarity of site of action and the similarity of slope has been debated since the introduction of the model (Cedergreen et al 2008;Hertzberg and MacDonell 2002;Jonker et al 2005;Sørensen et al 2007). The response to a mixed dose of two antioxidant agents (A 1 and A 2 ) in the absence of interactive effects (null interaction) can be postulated as the response of two fictitious "mixed" doses of the same agent, as described by (Murado and Prieto 2013a) as follows:…”

Section: Response Surface Model To Describe and Quantify The Interactmentioning

confidence: 99%

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An efficient methodology for quantification of synergy and antagonism in single electron transfer antioxidant assays

Prieto

Curran

Gowen

et al. 2015

Food Research International

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The development of new antioxidant compounds for incorporation in foods is a rapidly growing research area. The resulting interactions between complex antioxidant mixtures is a key issue, however, research in this area is still in its infancy. Experimental antioxidant models based on conventional dose-responses, that can predict joint effects of chemical mixtures, are urgently needed. This paper illustrates a methodological procedure for Single Electron Transfer (SET) antioxidant assays to determine the synergistic and antagonistic effects of combining binary mixtures of antioxidants. Despite the abundance of theories and procedures to describe the synergistic/antagonistic effects in SET assays, they appear to be inadequate. Some features hindering advances in this field include the lack of: (1) experimental design, as a result of the extended use of unambiguous and simplistic procedures to quantify the effects of joint responses, based on singledose values; (2) detailed mathematical hypotheses to quantify dose-response values, which in addition causes the associated difficulties for assessing the statistical consistence of the results; and (3) functional approaches that consider the possibility of interactive effects. This paper proposes solutions for each of these limitations. Established ideas from existing fields are used to replace the current simplistic procedures, in order to quantify the effects of joint responses. One of the common hypothesis (known as concentration addition) for describing the combined effects is established for SET assays. A dose dependent mathematical model representative of this hypothesis, based on probability functions with meaningful parameters, is applied. The interactive effects between antioxidants are introduced into the model with simple auxiliary functions that describe the variations induced by each antioxidant in the parameters that define the effects of the other. Finally, a comprehensive index to summarize the complex parametric responses in one single value is proposed. Although the approach was experimentally demonstrated just in two classical SET assays (DPPH and ABTS), the results could be directly expanded in future to other types of classical SET assays. The methodology proposed is more complex than some relatively common approaches; nevertheless we believe that it is free of the controversial aspects listed above. Statistically consistent responses of null, synergy and antagonism effects were found when characterizing the interactions between several pairs of individual and complex mixtures of chemical antioxidant agents.

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Section: Classical Interactive Hypothesis: Identification Of the Modementioning

confidence: 99%

Section: Response Surface Model To Describe and Quantify The Interactmentioning

confidence: 99%

An efficient methodology for quantification of synergy and antagonism in single electron transfer antioxidant assays

Prieto

Curran

Gowen

et al. 2015

Food Research International

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“…Because extensive information regarding both pharmacodynamics and pharmacokinetics is needed to actually judge the similarity of the mode of action of two or more chemicals [23], the preference of IA above CA based on the known or assumed mode of action has been questioned [23][24][25][26]. The classification of similar and dissimilar modes of action as applied in the present study relates to the pesticidal mode of action of the a.s., hence to the specific toxicity towards the target organisms based on the known molecular target and the development of cross-resistances in target organisms.…”

Section: Similarity In the Mode Of Actionmentioning

confidence: 99%

Predicting the aquatic toxicity of commercial pesticide mixtures

Coors

Frische

2011

Environ Sci Eur

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Background: Previous studies reported on a large (> 80%) compliance between the observed toxicity of pesticide mixtures and their toxicity as predicted by the concept of concentration addition (CA). The present study extents these findings to commercially sold and frequently applied pesticide mixtures by investigating whether the aquatic toxicity of 66 herbicidal and 53 fungicidal combination products, i.e., authorized plant protection products that contain two or more active substances, can reliably be predicted by CA. Results: In more than 50% of cases, the predicted and observed mixture toxicity deviated by less than factor 2. An indication for a synergistic interaction was only detected with regard to algal growth inhibition for mixtures of fungicides that inhibit different enzymes of ergosterol biosynthesis. The greatest degree of compliance between prediction and observation was found for the acute toxicity of fungicidal products towards Daphnia and fish, while the greatest degree of underestimation of product toxicity occurred for the acute toxicity of herbicidal products towards Daphnia and fish. Using the lowest available toxicity measures within taxonomic groups as the most conservative approach resulted in a bias towards overestimation of product toxicity, but did not eliminate cases of considerable underestimation of product toxicity. Conclusions:The results suggest that the CA concept can be applied to predict the aquatic toxicity of commercial pesticide mixtures using the heterogeneous data typically available in a risk assessment context for a number of clearly identified combinations of test species and pesticide types with reasonably small uncertainty.

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“…Antagony, synergy and additivity Cedergreen (2014) published a review of the occurrence of antagony, additivity and synergy in PPP mixtures, using the database published by Belden et al (2007) and the review by Cedergreen et al (2008). Synergy is here defined as mixtures with at least a two-fold difference between observed and predicted effect concentrations using concentration addition (CA) as a reference model and including both lethal and sublethal endpoints.…”

Section: 2mentioning

confidence: 99%

Including multistress in the risk assessment of plant protection products : current state of knowledge, based on a literature review and an evaluation of tank mixture applications in a spraying schedule for strawberries

Arts¹,

Beltman²,

Holterman³

et al. 2017

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This study presents a number of stepping stones towards answering the question if the current product-by-product and active substance-by-active substance evaluation provides sufficient protection in the context of the authorisation of plant protection products (PPPs) in the Netherlands. This report is based on a literature review and an evaluation of tank mixture applications in a spraying schedule for strawberries. The topic of tank mixtures has been identified by Ctgb (the Board for the Authorisation of Plant Protection Products and Biocides in The Netherlands) as an important knowledge gap. We have quantified the environmental risk for an intensively cultivated crop with sequential applications of products and mixtures of products based on a realistic application schedule and spray drift on surface water in a ditch, the corresponding exposure profiles and the effects based on the Regulatory Acceptable Concentrations of the used active substances. This study shows that the actual strawberry crop scenario is not protective for invertebrates and fish in surface water. Therefore, for the risk assessment of PPPs it needs to be considered that PPPs are part of a crop protection programme and thus should be evaluated in this context.

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

Cited by 83 publications

References 27 publications

An efficient methodology for quantification of synergy and antagonism in single electron transfer antioxidant assays

An efficient methodology for quantification of synergy and antagonism in single electron transfer antioxidant assays

Predicting the aquatic toxicity of commercial pesticide mixtures

Including multistress in the risk assessment of plant protection products : current state of knowledge, based on a literature review and an evaluation of tank mixture applications in a spraying schedule for strawberries

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