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This paper summarizes current challenges, the potential use of novel scientific methodologies, and ways forward in the risk assessment and risk management of mixtures. Generally, methodologies to address mixtures have been agreed; however, there are still several data and methodological gaps to be addressed. New approach methodologies can support the filling of knowledge gaps on the toxicity and mode(s) of action of individual chemicals. (Bio)Monitoring, modeling, and better data sharing will support the derivation of more realistic co-exposure scenarios. As knowledge and data gaps often hamper an in-depth assessment of specific chemical mixtures, the option of taking account of possible mixture effects in single substance risk assessments is briefly discussed. To allow risk managers to take informed decisions, transparent documentation of assumptions and related uncertainties is recommended indicating the potential impact on the assessment. Considering the large number of possible combinations of chemicals in mixtures, prioritization is needed, so that actions first address mixtures of highest concern and chemicals that drive the mixture risk. As chemicals with different applications and regulated separately might lead to similar toxicological effects, it is important to consider chemical mixtures across legislative sectors. ARTICLE HISTORY

Highlights Human Biomonitoring (HBM) provides valuable insight into co-exposure to multiple chemicals. HBM data can be interpreted in comparison to biomonitoring equivalents of health based guidance values. Two generic physiologically based kinetic models were tested for deriving biomonitoring equivalents. Uncertainties and limitations were identified and discussed. The use of biomonitoring equivalents in assessing chemical mixtures was illustrated in a case study.

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Regulatory human health risk assessment of chemicals ideally requires integration of toxicokinetic absorption, distribution, metabolism, and excretion where the respiratory system is a principal exposure route and threshold site for absorption. This study evaluated the permeability capacity of an in vitro human airway epithelium cell model (Muci-lAirÔ). Initially, definition of the in vitro method, including development of standard operating procedure confirmation of transferability and assurance of reproducible performance, was established in a preliminary phase involving two independent laboratories using six chemicals (propranolol, atenolol, nicotine, cadmium dichloride, cobalt chloride, and ammonium hexachloroplatinate). A follow-up investigation of method relevance, measuring relative permeability of 30 chemicals, in 1 laboratory is also reported. Absorption through the lung barrier model was determined as apparent permeability coefficient (P app ) following apical and basolateral exposure to nontoxic concentrations. P app was calculated from chemical concentrations crossing the cell barrier at appropriate time intervals. Comparative permeability of nasal and bronchial epithelium is also reported. Overall, the results demonstrate that MucilAir is an effective barrier model for assessing the permeability of different classes of compounds across the human airway epithelium. Results indicate a generally higher permeability of the airway epithelium for organic compounds compared to inorganic chemicals, with a low-protein-mediated efflux as permeability mechanism. The in vitro test system provides a robust and transferable method for determination of pulmonary absorption, relevant to toxicokinetic modeling and integration into risk assessment of chemicals.