A Cocktail a Day Keeps the Doc. Away – How to Consider Potential Additive Mixture Toxicology within Veterinary Pharmaceutical Legislation

Abstract

Conventional ecotoxicological assessments typically focus on single compounds and regulation is still ignoring and thus underestimating the effects of additive or synergistic mixture toxicology. Therefore, this study assesses how a Mixture Assessment Factor (MAF) might statistically be defined, considering the extensive variety of chemical mixtures possible, and what role single substance tests and measured environmental concentrations (MECs) can play in this process. The proposed approach includes publicly available databases, such as the Pharms-UBA (PU) for MECs and the European Medicines Agency's public assessment reports for effect data. Both were supplemented by internal data from the German Environment Agency, specifically from the Non-Target Screening portal for MECs and the Chemical Safety Information System for effect data. Three questions arose: (i) Based on theoretical additive effects, on what level the MAF should be set? (ii) Which mixtures are found in the environment, and in what range are the additive MECs? (iii) What are the PNECs of these mixtures and what MAFexact/min can be derived? The effect dataset contains 51 AS, which can theoretically form 2.25 x 1015 mixtures. Thus, the most relevant mixtures need to be found. The PU MEC database shows that, only based on soil and veterinary pharmaceuticals, 25 different AS can be found with theoretical 33.554.406 mixtures possible. In reality, 117 different cases were identified where mixtures actually occurred in the environment. Mixture sizes ranged from 2 to 8 out of 25 substances with additive MECs from ng up to mg/kg soil. In summary, our analysis demonstrates the need to incorporate additional safety factors into the regulatory framework to account for the already elevated levels of mixture exposure. This study could serve as a first step in identifying relevant mixtures, their occurrence, their mixture concentrations and consequently, the necessary adaptations of regulatory guidance to align with environmental protection goals.