Environmental risk assessment of antibiotics including synergistic and antagonistic combination effects

The interaction-based hazard index (HIint) allows a prediction of mixture effects different from linear additivity by including information on binary mixtures between the chemicals. The aim of this study is to make a solid estimate on the possible synergistic potential of combined antibiotics and to quantify the subsequent effect for the case of the receiving river Elbe, Germany. Pieces of information on binary interactions between antibiotic groups were used from literature and from knowledge on human antibiotic combination therapy. Applying a moderate and a worst-case scenario, in terms of the interaction magnitude, resulted in 50 to 200% higher environmental risks, compared to the classical assessment approach applying simple concentration addition. A subsequent sensitivity analysis revealed that the data strength for some binary antibiotic combinations is too low to be considered for a solid estimate of synergistic effects. This led to the definition of certain preconditions in order to decide whether or not to include certain interaction information (e.g. the necessary number of interaction studies). The exclusion of information with low data strength resulted in an attenuated risk increase of 20 to 50%, based on the currently available scientific information on binary antibiotic mixtures. In order to include antibiotics with the highest share in the overall risk (macrolides, quinolones, and cephalosporins) as well as their corresponding metabolites, investigations should focus on binary interactions between them.