title: Considering the cumulative risk of mixtures of chemicals - a challenge for policy makers.
abstract: BACKGROUND
  The current paradigm for the assessment of the health risk of chemical substances focuses primarily on the effects of individual substances for determining the doses of toxicological concern in order to inform appropriately the regulatory process. These policy instruments place varying requirements on health and safety data of chemicals in the environment. REACH focuses on safety of individual substances; yet all the other facets of public health policy that relate to chemical stressors put emphasis on the effects of combined exposure to mixtures of chemical and physical agents. This emphasis brings about methodological problems linked to the complexity of the respective exposure pathways; the effect (more complex than simple additivity) of mixtures (the so-called 'cocktail effect'); dose extrapolation, i.e. the extrapolation of the validity of dose-response data to dose ranges that extend beyond the levels used for the derivation of the original dose-response relationship; the integrated use of toxicity data across species (including human clinical, epidemiological and biomonitoring data); and variation in inter-individual susceptibility associated with both genetic and environmental factors.
  
  
  METHODS
  In this paper we give an overview of the main methodologies available today to estimate the human health risk of environmental chemical mixtures, ranging from dose addition to independent action, and from ignoring interactions among the mixture constituents to modelling their biological fate taking into account the biochemical interactions affecting both internal exposure and the toxic potency of the mixture.
  
  
  RESULTS
  We discuss their applicability, possible options available to policy makers and the difficulties and potential pitfalls in implementing these methodologies in the frame of the currently existing policy framework in the European Union. Finally, we suggest a pragmatic solution for policy/regulatory action that would facilitate the evaluation of the health effects of chemical mixtures in the environment and consumer products.
  
  
  CONCLUSIONS
  One universally applicable methodology does not yet exist. Therefore, a pragmatic, tiered approach to regulatory risk assessment of chemical mixtures is suggested, encompassing (a) the use of dose addition to calculate a hazard index that takes into account interactions among mixture components; and (b) the use of the connectivity approach in data-rich situations to integrate mechanistic knowledge at different scales of biological organization.
authors: European Commission - Joint Research Centre, Institute for Health and Consumer Protection, Chemical Assessment and Testing, via E. Fermi 1, 21027 (VA), Italy. denis@eng.auth.gr
authors: Denis A
authors: DA
authors: Sarigiannis
authors: Ute
authors: U
authors: Hansen
mesh_terms: D004782:Environmental Health / Q000379:methods*; D004785:Environmental Pollutants / Q000633:toxicity*; D005062:European Union; D006801:Humans; D011050:Policy Making; D018570:Risk Assessment
chemical_list: D004785:Environmental Pollutants