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Food and Chemical Toxicology 40 (2002) 825–839

Research section

Toxicological evaluation of chemical mixtures
V.J. Feron*, J.P. Groten
TNO Nutrition and Food Research, Utrechtseweg 48, PO Box 360, 3700 AJ Zeist, The Netherlands

Abstract This paper addresses major developments in the safety evaluation of chemical mixtures during the past 15 years,reviews today’s state of the art of mixture toxicology, and discusses challenges ahead. Well-thought-out tailor-made mechanistic and empirical designs for studying the toxicity of mixtures have gradually substituted trial-and-error approaches, improving the insight into the testability of joint action and interaction of constituents of mixtures. The acquired knowledge has successfully been used toevaluate the safety of combined exposures and complex mixtures such as, for example, the atmosphere at hazardous waste sites, drinking water disinfection by-products, natural flavouring complexes, and the combined intake of food additives. To consolidate the scientific foundation of mixture toxicology, studies are in progress to revisit the biological concepts and mathematics underlying formulas forlow-dose extrapolation and risk assessment of chemical mixtures. Conspicuous developments include the production of new computer programs applicable to mixture research (CombiTool, BioMol, Reaction Network Modelling), the application of functional genomics and proteomics to mixture studies, the use of nano-optochemical sensors for in vivo imaging of physiological processes in cells, and theapplication of optical sensor micro- and nano-arrays for complex sample analysis. Clearly, the input of theoretical biologists, biomathematicians and bioengineers in mixture toxicology is essential for the development of this challenging branch of toxicology into a scientific subdiscipline of full value. # 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Chemical mixtures; Toxicology; Safetyevaluation; Current issues; Challenges ahead

1. Introduction The vast majority of toxicity studies and risk evaluations deal with single chemicals. In reality, however, humans are exposed simultaneously or sequentially to large numbers of chemicals via multiple exposure routes. Determining human health risks from exposure to chemical mixtures is a daunting challenge to many experimentaltoxicologists and epidemiologists using observational methods.
Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry; CSU, Colorado State University; DBPs, disinfection by-products; DRD, detailed review document; EPA, Environmental Protection Agency; EU, European Union; HCL, Harmonisation of Classification and Labelling; HCN, Health Council of the Netherlands; ILSI, International LifeSciences Institute; NIEHS, National Institute of Environmental Health Sciences; NOAEL, no-observed-adverse-effect level; OECD, Organisation for Economic Cooperation and Development; OELs, occupational exposure limits; PBPK, physiologically-based pharmacokinetic; PCA, principal component analysis; PLS, projection to latent structures; PM, particulate matter; TTC, threshold of toxicological concern; TNO,Toegepast Natuurwetenschappelijk Onderzoek (Organisation for Applied Scientific Research); VOCs, volatile organic compounds; WHO, World Health Organization. * Corresponding author. Tel.: +31-30-69-59-408; fax: +31-30-6960-264. E-mail address: (V.J. Feron).

‘‘Mixtures are tough for everybody’’, Jonathan Samet said some years ago (Lang, 1995). This may be the reason why othersare especially attracted to this challenging vanguard of toxicology, and as Raymond Yang observed some 10 years ago: ‘‘Those who can withstand the heat may find that the reward far outweighs the frustrations’’ (Yang et al., 1989). Research programmes on the toxicology of chemical mixtures have existed for decades in the United States, and meanwhile have also been initiated in several other...
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