"A key challenge facing environmental risk assessors is the need to assess the risk of thousands of chemicals, for a wide range of species, with increased accuracy and ecological relevance, while using fewer resources and experimental animals. Traditional external toxicity metrics, such as the lethal aqueous concentration (LC50), are not sufficiently sophisticated to accomplish this task, and “new” approaches are emerging. This includes the tissue residue approach (TRA), which is advocated as a powerful tool to aid and improve ecological risk assessment. Claimed advantages include, a.o., a likely reduction in use of experimental animals, an improved ability to address mixture toxicity, and an improved ability to link laboratory measurements of exposure and effects to the field. Nevertheless, the application of the tissue-residue approach remains limited. This is mainly because internal target site concentrations are difficult to measure. Mechanistic models that enable the conversion of existing external effect data to critical target concentrations are therefore urgently needed. At present, such in silico tools are well-established for persistent organic chemicals acting via polar or non-polar narcosis. Reliable mechanistic models are however scarce for other modes of action. Therefore, we propose to develop mechanistic models that can reliably predict critical target residues from external effect concentrations for other chemicals, including reactive organic chemicals and metals."