Toxicology of chemical mixtures: international perspective.

This paper reviews major activities outside the United States on human health issues related to chemical mixtures. In Europe an international study group on combination effects has been formed and has started by defining synergism and antagonism. Successful research programs in Europe include the development and application of statistically designed experiments combined with multivariate data analysis and modeling in vitro and in vivo studies on a wide variety of chemicals such as petroleum hydrocarbons, aldehydes, food contaminants, industrial solvents, and mycotoxins. Other major activities focus on the development of safety evaluation strategies for mixtures such as the use of toxic equivalence factors or alternatives such as the question-and-answer approach, fractionation followed by recombination of the mixture in combination with a mixture design, and quantitative structure-activity relationship analysis combined with lumping analysis and physiologically based pharmacokinetic/pharmacodynamic modeling for studying complex mixtures. A scheme for hazard identification and risk assessment of complex mixtures and a consistent way to generate total volatile organic compound values for indoor air have also been developed. Examples of other activities are carcinogenicity studies on complex mixtures (petroleum middle distillates, foundry fumes, pesticides, heterocyclic amines, diesel exhaust, solid particles), neurotoxicity studies of mixtures of solvents alone or in combination with exposure to physical factors, and toxicity studies of outdoor air pollutants, focusing on particulates. Outside the United States, toxicologists and regulators clearly have a growing interest in the toxicology and risk assessment of chemical mixtures.