Mixture extrapolation approaches specificity

In our opinion, the data are sufficiently clear to suggest that when it is not feasible to test the mixture in question, mixture extrapolation is the preferred option compared to no extrapolation. Indeed, all literature observations suggest that applying mixture extrapolation is to be preferred over not applying mixture extrapolation. Technical options for extrapolation are concentration addition, response addition, and the mixed-model approach, of which concentration addition is most often applied. Exceptions may apply in cases that are more specific. For example, when it is clear that 2 compounds precipitate (a situation of no exposure due to chemical interactions in the environment), one should acknowledge this prior to assessing mixture risks by mixture extrapolation approaches. When the data of a study allow, refined conclusions are possible. For example, when the study design is appropriate and the mathematical models are appropriate, researchers are able to discriminate between concentration addition and response addition, and (with sufficient experiment efforts) between these models and the mixed-model approach. 

Higher tier mixture extrapolation approaches such as this are used in practice, by calculating site-specific msPAF values, across a broad range of assessment questions. A practical example is provided by De Zwart (2005), who studied the impacts of pesticide use in The Netherlands. In this study, the specific mode of action of the pesticide was taken into account, as shown in Box 5.2. This analysis resulted in spatiotemporal indicators of relative toxic pressure across The Netherlands (Figure 5.3). 

In the fourth step of extrapolation, specific mixture extrapolation protocols are needed. Below, some details on the theories and the associated protocols are given for concentration addition, response addition, and mixed-model approaches, and for the species and assemblage levels separately (this section and, next section, respectively). 

In contrast to the list of prediction methods that can be constructed from the literature on extrapolation of known mixtures, there is no specific technique that can be applied in practice as a method for mixture extrapolation for mixtures of unknown composition. Even if one has data (e.g., from a large series of WET observations at a certain location), the use of any extrapolation approach to predict the toxicity of a new WET test for that location may be inappropriate, especially when the situation of concern is unpredictable. 

A tiered system for mixture extrapolation is proposed. The lowest tier is based on extrapolation using toxicological point-estimate information such as EC50 values. This translates into the use of toxic units, toxic equivalencies, and similar techniques. The use of the entire concentration-response relationships of the separate compounds is recommended for Tier-2, in conjunction with the use of either concentration or response addition as a modeling approach. In Tier-3, a mixed-model approach can be considered, to more specifically address considerations on toxic modes of action. In the latter case, the approach may be extended to allow incorporation of the responses of different ecological receptors (Tier-4). Research needs have been clearly identified in community-level mixture assessments. 

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