classical models (both pharmaceuticals have similar MoA), CA model should
provide the best prediction about the toxic effects of the mixture of IB and DF.
In the case of the freshwater shrimp (Fig. 3), the CA model allows the best
prediction of the lethal effect of the mixture of DF and IB, although the adjustment
was more obvious at higher concentrations. Similarly, a better adjustment at higher
exposure concentrations was also observed in the case of the copepod T. battagliai,
but in this case, both models CA and IA provided very similar toxicity predictions
(Fig. 4). In this work, the authors tested a third model, a modification of the CA
model which includes a combination index that takes into account deviations from
additivity (CI in the Fig. 4): this model provided better predictions at lower exposure
concentrations.
The results of the works of Nieto et al. [19] and Trombini et al. [21], like those of
other authors [52], question the accuracy of the classic models (and those that
derives from them) for assessing toxicity of pharmaceutical mixtures, especially at
low exposure doses, making it difficult to assess the risk associated with the presence
of these two drugs in conditions closer to real scenarios.
35
30
DF-IB
1.45
IA
CA
L C
5
Prediction
O
b s e r v a t i o n
5.74
1.68
IA
CA
25
20
%Mortality
15
10
5
0
Fig. 3 Observed and predicted mortality for the freshwater shrimp Atyaephyra desmarestii
exposed to the mixture of Diclofenac (DF) and Ibuprofen (IB). Comparison between observed
toxicity (filled circles) and predicted mixture effects by the models CA (green solid line) and IA
(violet dash dot). Graph on the right represents the observed combined effects and predicted effects
of the mixture at LC 5 (mg L
À1
). Source: Nieto et al. [19] (with permission)
Ibuprofen and Diclofenac: Effects on Freshwater and Marine Aquatic Organisms –. . .
173
provide the best prediction about the toxic effects of the mixture of IB and DF.
In the case of the freshwater shrimp (Fig. 3), the CA model allows the best
prediction of the lethal effect of the mixture of DF and IB, although the adjustment
was more obvious at higher concentrations. Similarly, a better adjustment at higher
exposure concentrations was also observed in the case of the copepod T. battagliai,
but in this case, both models CA and IA provided very similar toxicity predictions
(Fig. 4). In this work, the authors tested a third model, a modification of the CA
model which includes a combination index that takes into account deviations from
additivity (CI in the Fig. 4): this model provided better predictions at lower exposure
concentrations.
The results of the works of Nieto et al. [19] and Trombini et al. [21], like those of
other authors [52], question the accuracy of the classic models (and those that
derives from them) for assessing toxicity of pharmaceutical mixtures, especially at
low exposure doses, making it difficult to assess the risk associated with the presence
of these two drugs in conditions closer to real scenarios.
35
30
DF-IB
1.45
IA
CA
L C
5
Prediction
O
b s e r v a t i o n
5.74
1.68
IA
CA
25
20
%Mortality
15
10
5
0
Fig. 3 Observed and predicted mortality for the freshwater shrimp Atyaephyra desmarestii
exposed to the mixture of Diclofenac (DF) and Ibuprofen (IB). Comparison between observed
toxicity (filled circles) and predicted mixture effects by the models CA (green solid line) and IA
(violet dash dot). Graph on the right represents the observed combined effects and predicted effects
of the mixture at LC 5 (mg L
À1
). Source: Nieto et al. [19] (with permission)
Ibuprofen and Diclofenac: Effects on Freshwater and Marine Aquatic Organisms –. . .
173