Project summary: a critical synopsis of mechanisms of action of low-dose xenobiotics in mammalian organisms as a basis for assessing aggregated effects of chemical mixtures and identifying "new" toxicological end points

Screening for chemicals which exert effects via common toxicity pathways and subsequently conducting targeted short-term tests may generate new information about the toxicity of chemicals without performing extensive substance-by-substance animal experiments. Information on common toxicity pathways may also provide input for the assessment of mixture effects. The U.S. Environmental Protection Agency is working intensely on this concept. It involves the use of enormous amounts of data on relevant biochemical and cellular processes, which are generated by "high-throughput screening" methods, and then are combined with substance-specific kinetic data, experimental apical test outcomes and modelling. Current limitations in the regulatory use of this integrated approach on risk assessment will be outlined.This manuscript comprises the theoretical background and conclusions made in a project initiated and published by the German Federal Environment Agency (see also "Acknowledgments"). The literature work was performed in between February of 2009 and March 2010. Further details beyond this summary can be taken from the original report available at the German Federal Environment Agency (FKZ 3708 61 205) [1]. Theoretical basis of this study is that European chemicals legislation requires the systematic study of marketed chemicals for, inter alia, properties of relevance to health (REACH: http://echa.europa.eu/legislation/reach_legislation_en.asp webcite). Animal studies that describe adverse effects on health (or their absence) are mainly used for this purpose, although the underlying mechanism of action does not have to be known. However, carrying out relevant in vivo studies is difficult to reconcile with animal welfare concerns and may be extremely costly. Moreover, their validity is limited and incomplete in several respects:？ The animal model is not always suited to detect all xenobiotic-related health effects on humans (in qualitative and quantitative terms).？ Currentl