Toxicology of chemical mixtures: International perspective

This paper reviews major activities outside the United States on human heal th issues related to chemical mixtures. in Europe an international study gr oup on combination effects has been formed and has started by defining syne rgism and antagonism. Successful research programs in Europe include the de velopment and application of statistically designed experiments combined wi th multivariate data analysis and modeling in in vitro and in vivo studies on a wide variety of chemicals such as petroleum hydrocarbons, aldehydes, f ood contaminants, industrial solvents, and mycotoxins. Other major activiti es focus on the development of safety evaluation strategies for mixtures su ch as the use of toxic equivalence factors or alternatives such as the ques tion-and-answer approach, fractionation followed by recombination of the mi xture in combination with a mixture design, and quantitative structure-acti vity relationship analysis combined with lumping analysis and physiological ly based pharmacokinetic/pharmacodynamic modeling for studying complex mixt ures. A scheme for hazard identification and risk assessment of complex mix tures and a consistent way to generate total volatile organic compound valu es for indoor air have also been developed, Examples of other activities ar e carcinogenicity studies on complex mixtures (petroleum middle distillates , foundry fumes, pesticides, heterocyclic amines, diesel exhaust, solid par ticles), neurotoxicity studies of mixtures of solvents alone or in combinat ion with exposure to physical factors, and toxicity studies of outdoor air pollutants, focusing on particulates. Outside the United States, toxicologi sts and regulators clearly have a growing interest in the toxicology and ri sk assessment of chemical mixtures.