Integrative Assessment of Mixture Toxicity of Three Ionic Liquids on Acetylcholinesterase Using a Progressive Approach from 1D Point, 2D Curve, to 3D Surface

Abstract

The joint toxicities of [BMIM]BF4, [BMIM]PF6, and [HMIM]BF4 on acetylcholinesterase (AChE) were systematically investigated by using a progressive approach from 1D single effect point, 2D concentration-response curve (CRC), to 3D equivalent-surface (ES) level. The equipartition equivalent-surface design (EESD) method was used to design 10 ternary mixtures, and the direct equipartition ray (EquRay) design was used to design 15 binary mixtures. The toxicities of ionic liquids (ILs) and their mixtures were determined using the microplate toxicity analysis (MTA) method. The concentration addition (CA), independent action (IA), and co-toxicity coefficient (CTC) were used as the additive reference model to analyze the toxic interaction of these mixtures. The results showed that the Weibull function fitted well the CRCs of the three ILs and their mixtures with the coefficient of determination (R2) greater than 0.99 and root-mean-square error (RMSE) less than 0.04. According to the CTC integrated with confidence interval (CI) method (CTCICI) developed in this study, the 25 mixtures were almost all additive action at 20% and 80% effect point levels. At 50% effect, at least half of the 25 mixtures were slightly synergistic action, and the remaining mixtures were additive action. Furthermore, the ESs and CRCs predicted by CA and IA were all within the CIs of mixture observed ESs and CRCs, respectively. Therefore, the toxic interactions of these 25 mixtures were actually additive action. The joint toxicity of the three ILs can be effectively evaluated by the ES method. We also studied the relationship between the mixture toxicities and component concentration proportions. This study can provide reference data for IL risk assessment of combined pollution.

Novel Segmented Concentration Addition Method to Predict Mixture Hormesis of Chlortetracycline Hydrochloride and Oxytetracycline Hydrochloride to Aliivibrio fischeri

“…The advantage of isobole was very obvious, which was easy to use, intuitive and convenient [29]. The disadvantage of isobole was also very obvious, which cannot be used for the mixtures with more than three components, even if the isobole can be extended to the equivalent-surface for three-component mixtures [49]. The advantages of CTC were simple, intuitive, and quantitative [49].…”

New Insight Regarding the Relationship Between Enantioselective Toxicity Difference and Enantiomeric Toxicity Interaction from Chiral Ionic Liquids

“…Using the EC x,i , EC x,mix , and P i , the CTC of IL enantiomer mixtures can be obtained as shown in Table 2. According to the CTCICI method [18], at 30%, 50%, and 80% effect levels, the mixtures of BD and BL, HL, and HD, and OD and OL overall presented antagonistic action, except for the additive action of H2, H3 at 80% effect, H1 at 50% effect, B4, B5, H1, O1, O2, and O4 at 30% effect. While ED and EL mixtures presented additive action at 30% and 50% effect levels, and presented synergistic action at 80% effect level except for the additive action of the E3 mixture.…”

“…However, based on IA, these mixtures were determined to be additive. Therefore, CA and IA should be used in combination to comprehensively judge the toxicity interaction of mixtures to avoid qualitative error [18]. On the other hand, the observed isoboles of the mixtures of BD and BL, and HD and HL deviated from the predicted isoboles of CA and IA far upward, and the CI of the observed isoboles basically cannot contain the CA or IA isobole, so these two pairs of enantiomers showed antagonistic action, and the mixture with molar ratio 1:1 generally had the largest deviation trend indicating the greatest toxic interaction.…”

“…Previous studies indicated that there was biphasic relationship between the binary mixture toxicity and the concentration proportion (P i ) of components [18]. A pair of enantiomers of chiral molecules can form the natural binary mixtures.…”

“…At the single effect point level, the toxic interactions of mixtures were evaluated using the components EC x,i , and mixture observed EC x,mix and its 95% CI according to the CTCICI method developed recently [18]. The CTC were computed using Equation (5).…”