New developments for harmonised risk assessment on emerging chemical hazards: "Chemical mixtures"

Multiple chemicals known as “chemical mixtures” are ubiquitous, in our body and in the environment through food, the air, drinking water, while our skin can also be exposed to contaminants in soil and dust. Toxins can enter an organism via single or combined oral, dermal and inhalation routes. Hence, the number of chemicals and their combinations is practically infinite, rendering their assessment a very challenging task. There are numerous studies in the literature demonstrating that chemicals, when administered together, mostly induce additive combined toxicity while antagonistic, potentiation or even synergistic effects are less common; depending on composition, exposure and mode of action (MoA). Thus, combined toxicity should be taken into account when a risk assessment is performed particularly during the risk characterisation step to avoid underestimation of the risk. In recent years, the European Commission has requested further development of methods for the risk assessment of chemical mixtures and has highlighted the importance of identifying data gaps and related uncertainties in our current knowledge. In addition, risk assessment of chemical mixtures is included in recent food safety regulations. Over the years, various national and international scientific advisory bodies as well as regulatory agencies have published reports and guidance documents, addressing the risk assessment of chemical mixtures for human health, animal health and the environment. The present thesis is divided into six chapters, which discuss different aspects of the risk assessment of chemical mixtures. Chapter 1 provides an overview of the methods dealing with risk assessment of combined exposure to chemicals. Chapter 2 reviews available knowledge and data gaps on single and multiple mycotoxins including their co-occurrence in the field, pre- and post-mitigation practices as well as their toxicokinetics in test species and farm animals. Chapter 3 investigates the relevance of metabolic interactions between human pharmaceuticals and chemicals of relevance to food safety (i.e. pesticides and flavonoids) particularly, concerning enzymes involved in xenobiotic metabolism (phase I, phase II and transporters). This has been specifically addressed through in vitro data collection reporting quantitative inhibition parameters (Ki, IC50, % of inhibition) and extrapolation from in vitro to in vivo kinetics. Chapter 4 provides an analysis of combined toxicity data on binary pesticide mixtures in test species. The analysis focuses on the quantification of the magnitudes of interaction after acute, subacute, sub-chronic or chronic exposure and expressed as a mean effect ratio for single compounds and binary mixtures. Further, this provides a transparent reporting of measured toxicological endpoints as well as a mean to test of the dose dependency of toxicological interactions. In Chapter 5, human exposure to phthalates is estimated using a probabilistic approach and the outcome is then compared with measured phthalate concentrations resulting from a biomonitoring study conducted in Norway. Finally, risk characterisation is performed for single phthalates as well as their combined exposure. Chapter 6 provides a discussion of the methodologies applied in this thesis in comparison to those available in the peer-reviewed literature and, underlines challenges for the risk assessment of combined exposure to chemical mixtures and highlights the need for further work in this area of high relevance to human health, animal health and the environment.