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Safety evaluation of chemical mixtures and combinations of chemical and non-chemical stressors

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Author: Jonker, D. · Freidig, A.P. · Groten, J.P. · Hollander, · Stierum, R.H. · Woutersen, R.A. · Feron, V.J.
Institution: TNO Voeding
Source:Reviews on Environmental Health, 2, 19, 83-139
Identifier: 237702
Keywords: Chemistry Biology · Toxicology and Applied Pharmacology · Combination toxicology · Cumulative risk assessment · chemical agent · bioinformatics · cold stress · environmental exposure · genomics · health hazard · heat stress · human · immobilization stress · indoor air pollution · microorganism · noise · nonhuman · rat · review · risk assessment · safety · stress · toxicokinetics · toxicology · traffic · Dose-Response Relationship, Drug · Drug Interactions · Environmental Exposure · Humans · Models, Statistical · Risk Assessment · Safety · Sequence Analysis, Protein · Structure-Activity Relationship · Toxicology · Xenobiotics


Recent developments in hazard identification and risk assessment of chemical mixtures are reviewed. Empirical, descriptive approaches to study and characterize the toxicity of mixtures have dominated during the past two decades, but an increasing number of mechanistic approaches have made their entry into mixture toxicology. A series of empirical studies with simple chemical mixtures in rats is described in some detail because of the important lessons from this work. The development of regulatory guidelines for the toxicological evaluation of chemical mixtures is discussed briefly. Current issues in mixture toxicology include the adverse health effects of ambient air pollution; the application of such modern, sophisticated methodologies as genomics, bioinformatics, and physiologically based pharmacokinetic modeling; and databases for mixture toxicity. Finally, the state of the art of our knowledge on the potential adverse health effects of combined exposures to chemicals and non-chemical stressors (noise, heat/cold, microorganisms, immobilization, restraint, or transportation), research initiatives in these fields, and the development of an indicator for the cumulative health impact of multiple environmental exposures are discussed.