Assessing the Effect of Mycotoxin Combinations: Which Mathematical Model Is (the Most) Appropriate?

Abstract

In the past decades, many studies have examined the nature of the interaction between mycotoxins in biological models classifying interaction effects as antagonisms, additive effects, or synergisms based on a comparison of the observed effect with the expected effect of combination. Among several described mathematical models, the arithmetic definition of additivity and factorial analysis of variance were the most commonly used in mycotoxicology. These models are incorrectly based on the assumption that mycotoxin dose-effect curves are linear. More appropriate mathematical models for assessing mycotoxin interactions include Bliss independence, Loewe’s additivity law, combination index, and isobologram analysis, Chou-Talalays median-effect approach, response surface, code for the identification of synergism numerically efficient (CISNE) and MixLow method. However, it seems that neither model is ideal. This review discusses the advantages and disadvantages of these mathematical models.

Co-Loaded Curcumin and Methotrexate Nanocapsules Enhance Cytotoxicity against Non-Small-Cell Lung Cancer Cells

“…To define the drug-drug interaction potential from the use of NCs containing CUR and MTX against Calu-3 cells, the combination index (CI) was calculated by Equation (3) [58] considering the results obtained by the MTT method:…”

In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone

“…For toxic compounds there have been developed several mathematical methods implemented in informatics programs for assessing the effect of compounds combination and effects contributing to computational toxicology: Chou and Talalay by using isobolograms, Simple Addition of Effect, Factorial Analysis of Variance by using simple 2-way ANOVA, Bliss Independence Criterion, Loewe’s Additivity Law, Highest Single Agent (HSA) Model (Gaddums non-interaction), etc. ( Kifer et al, 2020 ). For mycotoxins´ mixture assessment, Choy and Talalay method has been widely used in predicting potential effects (synergism, addition and antagonism) ( Juan-García et al, 2019a , 2019b , 2016 ; Agahi et al, 2020 ) even with strong differences in chemical structures as well as in the variety of fungi spp .…”

Cytotoxic effects of individual and binary combinations of zearalenone and ochratoxin a on liver

“…Other recent study that investigated individual and combined cytotoxicity effect of zearalenone and ochratoxin A on HepG2 but using a full factorial design as mathematical model found an antagonism for the combination of ZEA (30 and 60M) and OTA (6 and 12 M) (Zheng et al 2018). However, these results were based on the assumption that mycotoxin dose-effect curves are linear (simple addition of effects, factorial analysis of variance) which is not useful for modelling nonlinear dose-effect curves (Kifer et al 2020). Our study has used the Chou-Talalay model combined with an isobologram that has been applied in the majority of the recently published studies concerning the mycotoxin combinations; use of this model allow the estimation of confidence intervals for the combination index which enables the application of statistics (Kifer et al 2020).…”

“…However, these results were based on the assumption that mycotoxin dose-effect curves are linear (simple addition of effects, factorial analysis of variance) which is not useful for modelling nonlinear dose-effect curves (Kifer et al 2020). Our study has used the Chou-Talalay model combined with an isobologram that has been applied in the majority of the recently published studies concerning the mycotoxin combinations; use of this model allow the estimation of confidence intervals for the combination index which enables the application of statistics (Kifer et al 2020).…”